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Mendeliome v1.2302 AAAS Classified gene: AAAS as Red List (low evidence)
Mendeliome v1.2302 AAAS Added comment: Comment on list classification: haefwewlfjwfe
Mendeliome v1.2302 AAAS Gene: aaas has been classified as Red List (Low Evidence).
Mendeliome v1.2301 HSPB8 Zornitza Stark Phenotypes for gene: HSPB8 were changed from Distal myopathy; Vacuolar myopathy; Neuropathy, distal hereditary motor type IIA, 158590; Charcot-Marie-Tooth disease, axonal, type 2L, MIM# 608673 to Myopathy, myofibrillar, 13, with rimmed vacuoles, MIM# 621078; Distal myopathy; Vacuolar myopathy; Neuropathy, distal hereditary motor type IIA, 158590; Charcot-Marie-Tooth disease, axonal, type 2L, MIM# 608673
Mendeliome v1.2300 HSPB8 Zornitza Stark edited their review of gene: HSPB8: Changed phenotypes: Myopathy, myofibrillar, 13, with rimmed vacuoles, MIM# 621078, Distal myopathy, Vacuolar myopathy, Neuropathy, distal hereditary motor type IIA, 158590, Charcot-Marie-Tooth disease, axonal, type 2L, MIM# 608673
Mendeliome v1.2300 CLCA2 Bryony Thompson Marked gene: CLCA2 as ready
Mendeliome v1.2300 CLCA2 Bryony Thompson Gene: clca2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2300 CLCA2 Bryony Thompson Classified gene: CLCA2 as Amber List (moderate evidence)
Mendeliome v1.2300 CLCA2 Bryony Thompson Gene: clca2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2299 CLCA2 Bryony Thompson gene: CLCA2 was added
gene: CLCA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLCA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLCA2 were set to 31326550
Phenotypes for gene: CLCA2 were set to heart conduction disease MONDO:0000992
Review for gene: CLCA2 was set to AMBER
Added comment: Only a single family reported. A missense (p.Trp575Cys) segregates with conduction disease in 5 individuals from a large Chinese family. Electrocardiogram monitoring of mice with missense introduced induced mild conduction block and ectopic pacemakers.
Sources: Literature
Mendeliome v1.2298 HECTD1 Zornitza Stark Marked gene: HECTD1 as ready
Mendeliome v1.2298 HECTD1 Zornitza Stark Gene: hectd1 has been classified as Green List (High Evidence).
Mendeliome v1.2298 ARHGEF40 Zornitza Stark Marked gene: ARHGEF40 as ready
Mendeliome v1.2298 ARHGEF40 Zornitza Stark Gene: arhgef40 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2298 ARHGEF40 Zornitza Stark Classified gene: ARHGEF40 as Amber List (moderate evidence)
Mendeliome v1.2298 ARHGEF40 Zornitza Stark Gene: arhgef40 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2297 ARHGEF40 Zornitza Stark reviewed gene: ARHGEF40: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2297 C12orf66 Zornitza Stark Marked gene: C12orf66 as ready
Mendeliome v1.2297 C12orf66 Zornitza Stark Added comment: Comment when marking as ready: HGNC approved name: KICS2
Mendeliome v1.2297 C12orf66 Zornitza Stark Gene: c12orf66 has been classified as Green List (High Evidence).
Mendeliome v1.2297 C12orf66 Zornitza Stark Tag new gene name tag was added to gene: C12orf66.
Mendeliome v1.2297 DDX53 Zornitza Stark Marked gene: DDX53 as ready
Mendeliome v1.2297 DDX53 Zornitza Stark Gene: ddx53 has been classified as Green List (High Evidence).
Mendeliome v1.2297 SHROOM3 Chirag Patel reviewed gene: SHROOM3: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 39875538; Phenotypes: Craniofacial microsomia MONDO:0015397; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2297 C12orf66 Chirag Patel reviewed gene: C12orf66: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39824192; Phenotypes: Neurodevelopmental disorder MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2297 ARHGEF40 Chirag Patel Classified gene: ARHGEF40 as Red List (low evidence)
Mendeliome v1.2297 ARHGEF40 Chirag Patel Gene: arhgef40 has been classified as Red List (Low Evidence).
Mendeliome v1.2296 ARHGEF40 Chirag Patel Classified gene: ARHGEF40 as Green List (high evidence)
Mendeliome v1.2296 ARHGEF40 Chirag Patel Gene: arhgef40 has been classified as Green List (High Evidence).
Mendeliome v1.2295 ARHGEF40 Chirag Patel gene: ARHGEF40 was added
gene: ARHGEF40 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARHGEF40 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGEF40 were set to PMID: 39838643
Phenotypes for gene: ARHGEF40 were set to Neurodevelopmental disorder MONDO:0700092
Review for gene: ARHGEF40 was set to RED
Added comment: 2 individuals with global developmental delay, hypotonia, short stature, hearing impairment, nystagmus, feeding issues, and dysmorphism (bifid uvula, narrow mouth, high palate, micrognathia). Trio clinical whole exome sequencing identified de novo variants in the ARHGEF40 gene at position p.Arg225, which is fully conserved in mammals and located within the n-terminal keratin binding region (p.Arg225Trp and p.Arg225Gln). Of note, multiple additional probands with rare missense variants at the p.Arg225 residue have been identified by the same laboratory (but there was no consent for publication, providing further evidence of
the importance of this residue.

The ARHGEF40 gene (aka SOLO) is a member of the Rho guanine nucleotide exchange factor (Rho-GEF) family of proteins, which stimulate Rho signal transduction molecules by converting them from inactive GDP-bound form to the active GTP-bound state. No functional studies to characterise disease-gene relationship or disease mechanism.
Sources: Literature
Mendeliome v1.2294 HECTD1 Chirag Patel Classified gene: HECTD1 as Green List (high evidence)
Mendeliome v1.2294 HECTD1 Chirag Patel Gene: hectd1 has been classified as Green List (High Evidence).
Mendeliome v1.2293 HECTD1 Chirag Patel gene: HECTD1 was added
gene: HECTD1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HECTD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HECTD1 were set to PMID: 39879987
Phenotypes for gene: HECTD1 were set to Neurodevelopmental disorder MONDO:0700092
Review for gene: HECTD1 was set to GREEN
Added comment: 14 unrelated individuals (identified through GeneMatcher) with 15 variants of uncertain significance (VUS) in HECTD1 (10 missense, 3 frameshift, 1 nonsense, and 1 splicing variant). Of the 15 different variants in HECTD1, 10 occurred de novo, 3 had unknown inheritance, and 2 were compound heterozygous. All variants were absent in gnomAD, and HECTD1 is highly intolerant to loss-of-function variation (loss-of-function-intolerant score of 1). Clinical presentation was variable developmental delay, intellectual disability, autism spectrum disorder, ADHD, and epilepsy.

The one individual with compound heterozygous variants had growth impairment along with NDD. The variants were inherited from apparently healthy parents, suggesting that genetic or environmental modifiers may be required to develop the phenotype. Significant enrichment of de novo variants in HECTD1 was also shown in an independent cohort of 53,305 published trios with NDDs or congenital heart disease.

HECT-domain-containing protein 1 (HECTD1) mediates developmental pathways, including cell signalling, gene expression, and embryogenesis. Conditional knockout of Hectd1 in the neural lineage in mice resulted in microcephaly, severe hippocampal malformations, and complete agenesis of the corpus callosum, supporting a role for Hectd1 in embryonic brain development. Functional studies of 2 missense variants and 1 nonsense variant in C. elegans revealed dominant effects, including either change-of-function or loss-of-function/haploinsufficient mechanisms.
Sources: Literature
Mendeliome v1.2292 PDGFRB Zornitza Stark Phenotypes for gene: PDGFRB were changed from Basal ganglia calcification, idiopathic, 4, MIM# 615007; Kosaki overgrowth syndrome, MIM# 616592; Myeloproliferative disorder with eosinophilia, MIM# 131440; Myofibromatosis, infantile, 1, MIM# 228550; Premature ageing syndrome, Penttinen type, MIM# 601812 to Basal ganglia calcification, idiopathic, 4, MIM# 615007; Kosaki overgrowth syndrome, MIM# 616592; Myeloproliferative disorder with eosinophilia, MIM# 131440; Myofibromatosis, infantile, 1, MIM# 228550; Premature ageing syndrome, Penttinen type, MIM# 601812; Ocular pterygium-digital keloid dysplasia syndrome, MIM# 621091
Mendeliome v1.2291 PDGFRB Zornitza Stark edited their review of gene: PDGFRB: Added comment: Single family reported with OPDKD phenotype characterised by aggressive circumferential ingrowth of conjunctiva beginning in early childhood that is resistant to treatment, ultimately covering the cornea and resulting in loss of vision. Digital keloid formation after minor trauma, which can become extensive and cause flexion contractures; hardened auricles. RED for this association.; Changed publications: 33450762; Changed phenotypes: Ocular pterygium-digital keloid dysplasia syndrome, MIM# 621091, Basal ganglia calcification, idiopathic, 4, MIM# 615007, Kosaki overgrowth syndrome, MIM# 616592, Myeloproliferative disorder with eosinophilia, MIM# 131440, Myofibromatosis, infantile, 1, MIM# 228550, Premature ageing syndrome, Penttinen type, MIM# 601812
Mendeliome v1.2291 TAF11 Bryony Thompson Marked gene: TAF11 as ready
Mendeliome v1.2291 TAF11 Bryony Thompson Gene: taf11 has been classified as Red List (Low Evidence).
Mendeliome v1.2291 TAF11 Bryony Thompson gene: TAF11 was added
gene: TAF11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TAF11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TAF11 were set to 39727181
Phenotypes for gene: TAF11 were set to cleft lip MONDO:0004747
Review for gene: TAF11 was set to RED
Added comment: 2 individuals in a single Chinese family with nonsyndromic cleft lip segregating with the missense p.Leu48Phe. The missense has an AF of 1.8% (including 15 homozygotes) in gnomAD v4 in the East Asian population, which is too common for an autosomal dominant disease—also, a supporting zebrafish model with craniofacial abnormalities (however the genetic evidence for this GDA is lacking).
Sources: Literature
Mendeliome v1.2290 PTPMT1 Bryony Thompson Marked gene: PTPMT1 as ready
Mendeliome v1.2290 PTPMT1 Bryony Thompson Gene: ptpmt1 has been classified as Green List (High Evidence).
Mendeliome v1.2290 PTPMT1 Bryony Thompson Classified gene: PTPMT1 as Green List (high evidence)
Mendeliome v1.2290 PTPMT1 Bryony Thompson Gene: ptpmt1 has been classified as Green List (High Evidence).
Mendeliome v1.2289 PTPMT1 Bryony Thompson gene: PTPMT1 was added
gene: PTPMT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTPMT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPMT1 were set to 39279645; 37672386
Phenotypes for gene: PTPMT1 were set to inborn mitochondrial metabolism disorder MONDO:0004069
Review for gene: PTPMT1 was set to GREEN
Added comment: 6 cases from 3 independent families with biallelic variants in PTPMT1 (a mitochondrial tyrosine phosphatase required for de novo cardiolipin biosynthesis). All cases presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome including developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Supporting knockout zebrafish and mouse models.
Sources: Literature
Mendeliome v1.2288 NR6A1 Bryony Thompson Marked gene: NR6A1 as ready
Mendeliome v1.2288 NR6A1 Bryony Thompson Gene: nr6a1 has been classified as Green List (High Evidence).
Mendeliome v1.2288 NR6A1 Bryony Thompson Classified gene: NR6A1 as Green List (high evidence)
Mendeliome v1.2288 NR6A1 Bryony Thompson Gene: nr6a1 has been classified as Green List (High Evidence).
Mendeliome v1.2287 NR6A1 Bryony Thompson gene: NR6A1 was added
gene: NR6A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NR6A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NR6A1 were set to 39606382
Phenotypes for gene: NR6A1 were set to Craniofacial microsomia MONDO:0015397
Review for gene: NR6A1 was set to GREEN
Added comment: 6 unrelated families with heterozygous rare variants (missense, nonsense, frameshift, or large deletion) with incomplete penetrance and variable expressivity. Colobomatous microphthalmia, missing vertebrae and congenital kidney abnormalities characterised the phenotype of the families. Also, supporting zebrafish model. Loss of function is the expected mechanism of disease.
Sources: Literature
Mendeliome v1.2286 MRAP2 Zornitza Stark Marked gene: MRAP2 as ready
Mendeliome v1.2286 MRAP2 Zornitza Stark Gene: mrap2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2286 MRAP2 Zornitza Stark Classified gene: MRAP2 as Amber List (moderate evidence)
Mendeliome v1.2286 MRAP2 Zornitza Stark Gene: mrap2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2285 MRAP2 Zornitza Stark gene: MRAP2 was added
gene: MRAP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MRAP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MRAP2 were set to 23869016; 31700171; 27474872; 26795956
Phenotypes for gene: MRAP2 were set to Susceptibility to obesity, MIM#615457
Review for gene: MRAP2 was set to AMBER
Added comment: Multiple studies supporting association between rare variants and obesity; however ?monogenic vs susceptibility alleles.
Sources: Literature
Mendeliome v1.2284 ITGAV Zornitza Stark Marked gene: ITGAV as ready
Mendeliome v1.2284 ITGAV Zornitza Stark Gene: itgav has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2284 ITGAV Zornitza Stark Classified gene: ITGAV as Amber List (moderate evidence)
Mendeliome v1.2284 ITGAV Zornitza Stark Gene: itgav has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2283 ITGAV Zornitza Stark gene: ITGAV was added
gene: ITGAV was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ITGAV was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITGAV were set to 39526957
Phenotypes for gene: ITGAV were set to Syndromic disease, MONDO:0002254, ITGAV-related
Review for gene: ITGAV was set to AMBER
Added comment: Three unrelated families reported: two with affected children (one hmz missense; other compound het LoF with missense) and one family with four affected fetuses. Clinical features included brain and eye anomalies and IBD/immune dysregulation. TGF-beta signalling pathway affected. The deletion of itgav in zebrafish recapitulated patient phenotypes including retinal and brain defects and the loss of microglia in early development as well as colitis in juvenile zebrafish with reduced SMAD3 expression and transcriptional regulation.
Sources: Literature
Mendeliome v1.2282 RYBP Zornitza Stark Marked gene: RYBP as ready
Mendeliome v1.2282 RYBP Zornitza Stark Gene: rybp has been classified as Green List (High Evidence).
Mendeliome v1.2282 RYBP Zornitza Stark Classified gene: RYBP as Green List (high evidence)
Mendeliome v1.2282 RYBP Zornitza Stark Gene: rybp has been classified as Green List (High Evidence).
Mendeliome v1.2281 RYBP Zornitza Stark gene: RYBP was added
gene: RYBP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RYBP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RYBP were set to 39891528
Phenotypes for gene: RYBP were set to Neurodevelopmental disorder, MONDO:0700092, RYBP-related
Review for gene: RYBP was set to GREEN
Added comment: Seven individuals with heterozygous de novo variants in RYBP reported. Clinical findings include severe developmental delay, dysmorphisms and multiple congenital anomalies. All the single nucleotide variants in RYBP localized to the N-terminal domain of the gene, which encodes the zinc finger domain and ubiquitin binding moiety. Further supportive in vitro and Drosophila functional data.
Sources: Literature
Mendeliome v1.2280 C1orf127 Zornitza Stark Marked gene: C1orf127 as ready
Mendeliome v1.2280 C1orf127 Zornitza Stark Gene: c1orf127 has been classified as Green List (High Evidence).
Mendeliome v1.2280 C1orf127 Zornitza Stark Classified gene: C1orf127 as Green List (high evidence)
Mendeliome v1.2280 C1orf127 Zornitza Stark Gene: c1orf127 has been classified as Green List (High Evidence).
Mendeliome v1.2279 C1orf127 Zornitza Stark gene: C1orf127 was added
gene: C1orf127 was added to Mendeliome. Sources: Literature
new gene name tags were added to gene: C1orf127.
Mode of inheritance for gene: C1orf127 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1orf127 were set to 39753129
Phenotypes for gene: C1orf127 were set to Heterotaxy, visceral, MONDO:0018677, CIROZ-related
Review for gene: C1orf127 was set to GREEN
Added comment: 16 individuals from 10 families reported with bi-allelic variants in this gene and heterotaxy, including CHD. Supportive mouse model. CIROZ is absent or obsolete in select animals with motile cilia at their left-right organiser, including Carnivora, Atherinomorpha fish, or jawless vertebrates. Knockouts in zebrafish and Xenopus did not have observable LR anomalies. Approved HGNC name is CIROZ.
Sources: Literature
Mendeliome v1.2278 DAND5 Zornitza Stark Marked gene: DAND5 as ready
Mendeliome v1.2278 DAND5 Zornitza Stark Gene: dand5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2278 DAND5 Zornitza Stark Classified gene: DAND5 as Amber List (moderate evidence)
Mendeliome v1.2278 DAND5 Zornitza Stark Gene: dand5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2277 DAND5 Zornitza Stark gene: DAND5 was added
gene: DAND5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DAND5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAND5 were set to 36316122; 34215651
Phenotypes for gene: DAND5 were set to Heterotaxy, visceral, 13, autosomal, MIM# 621079
Review for gene: DAND5 was set to AMBER
Added comment: Two individuals reported with bi-allelic LoF variants and heterotaxy.
Sources: Literature
Mendeliome v1.2276 SEL1L Zornitza Stark Phenotypes for gene: SEL1L were changed from Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, MIM# 621067 to Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinaemia, MIM# 621068; Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, MIM# 621067
Mendeliome v1.2275 SEL1L Zornitza Stark edited their review of gene: SEL1L: Added comment: Has been split into two conditions by OMIM -- uncertain that these are distinct and not part of a spectrum. Await further reports.; Changed phenotypes: Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinaemia, MIM# 621068, Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, MIM# 621067
Mendeliome v1.2275 SEL1L Zornitza Stark Phenotypes for gene: SEL1L were changed from Neurodevelopmental disorder, MONDO:0700092, SEL1L-related to Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, MIM# 621067
Mendeliome v1.2274 SEL1L Zornitza Stark reviewed gene: SEL1L: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, MIM# 621067; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2274 PPA1 Zornitza Stark Marked gene: PPA1 as ready
Mendeliome v1.2274 PPA1 Zornitza Stark Gene: ppa1 has been classified as Red List (Low Evidence).
Mendeliome v1.2274 PPA1 Zornitza Stark gene: PPA1 was added
gene: PPA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPA1 were set to 37999237
Phenotypes for gene: PPA1 were set to Galactosaemia, MONDO:0018116
Review for gene: PPA1 was set to RED
Added comment: Homozygous missense variant detected in two siblings with increased galactose and galactose-related metabolites ascertained in neonatal screening. Some supportive functional data.
Sources: Literature
Mendeliome v1.2273 DMRT1 Zornitza Stark Phenotypes for gene: DMRT1 were changed from Azoospermia to 46,XY disorder of sex development, MONDO:0020040
Mendeliome v1.2272 DMRT1 Zornitza Stark Classified gene: DMRT1 as Amber List (moderate evidence)
Mendeliome v1.2272 DMRT1 Zornitza Stark Gene: dmrt1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2271 DMRT1 Zornitza Stark edited their review of gene: DMRT1: Added comment: DMRT1 gene exclusively expressed in male gonads. Thought not to affect ovarian development.
Gene included three international studies - see PMID: 28295047 supplemental article Fig 1 patient 19, 46XY with hypoplastic labia, uterus present had DMRT1 c.251A>G p.Tyr84Cys maternally inherited VOUS
PMID: 26005864: p.R111G also described in complete gonadal dysgenesis; Changed rating: AMBER; Changed publications: 31479588, 24934491, 29527098, 26005864, 28295047; Changed phenotypes: 46,XY disorder of sex development, MONDO:0020040
Mendeliome v1.2271 GUK1 Zornitza Stark Phenotypes for gene: GUK1 were changed from Mitochondrial DNA depletion syndrome MONDO:0018158, GUK1-related to Mitochondrial DNA depletion syndrome 21, MIM# 621071
Mendeliome v1.2270 GUK1 Zornitza Stark reviewed gene: GUK1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial DNA depletion syndrome 21, MIM# 621071; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2270 FLVCR1 Zornitza Stark Phenotypes for gene: FLVCR1 were changed from posterior column ataxia-retinitis pigmentosa syndrome MONDO:0012177; neurodevelopmental disorder MONDO:0700092, FLVCR1-related to posterior column ataxia-retinitis pigmentosa syndrome MONDO:0012177; Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MIM#621060
Mendeliome v1.2269 FLVCR1 Zornitza Stark reviewed gene: FLVCR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MIM#621060; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2269 MGA Zornitza Stark Marked gene: MGA as ready
Mendeliome v1.2269 MGA Zornitza Stark Gene: mga has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2269 MGA Zornitza Stark Classified gene: MGA as Amber List (moderate evidence)
Mendeliome v1.2269 MGA Zornitza Stark Gene: mga has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2268 MGA Zornitza Stark gene: MGA was added
gene: MGA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MGA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MGA were set to 39600096; 20044811; 39545409
Phenotypes for gene: MGA were set to Syndromic disease, MONDO:0002254, MGA-related; Premature ovarian failure 26, MIM# 621065
Review for gene: MGA was set to AMBER
Added comment: Association with syndromic disease: Three individuals with de novo LoF variants reported in individuals with ID and congenital anomalies. Zebrafish model supports role of this transcription factor in organogenesis. Note there are previous, less clear reports of association with NDD/CHD. Gene is constrained for LoF variants in gnomad v4; however, note there are ~30 individuals with LoF variants present. Borderline Green/Amber.

Association with POF: LoF variants enriched in a large POF cohort. Familial testing in a small number of families performed. Mouse model supportive. Also borderline Amber/Green.

Amber rating until phenotypes and mechanisms of disease for these two associations clarified.
Sources: Literature
Mendeliome v1.2267 USP25 Zornitza Stark Phenotypes for gene: USP25 were changed from USP25-related epilepsy (epilepsy, idiopathic generalized, MONDO:0005579) to {Epilepsy, idiopathic generalized, susceptibility to, 19} MIM#621064
Mendeliome v1.2266 LMNB1 Zornitza Stark Phenotypes for gene: LMNB1 were changed from Microcephaly 26, primary, autosomal dominant, MIM# 619179; Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis; Leukodystrophy, adult-onset, autosomal dominant, MIM#169500 to Microcephaly 26, primary, autosomal dominant, MIM# 619179; Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis; Leukodystrophy, adult-onset, autosomal dominant, MIM# 169500; Leukodystrophy, demyelinating, adult-onset, autosomal dominan, atypical, MIM#621061
Mendeliome v1.2265 LMNB1 Zornitza Stark edited their review of gene: LMNB1: Changed phenotypes: Microcephaly 26, primary, autosomal dominant, MIM# 619179, Global developmental delay, Intellectual disability, Microcephaly, Short stature, Seizures, Abnormality of the corpus callosum, Cortical gyral simplification, Feeding difficulties, Scoliosis, Leukodystrophy, adult-onset, autosomal dominant, MIM# 169500, Leukodystrophy, demyelinating, adult-onset, autosomal dominan, atypical, MIM#621061
Mendeliome v1.2265 HYAL2 Zornitza Stark Phenotypes for gene: HYAL2 were changed from Cleft lip and palate; cor triatriatum; congenital cardiac malformations to Muggenthaler-Chowdhury-Chioza syndrome, MIM# 621063
Mendeliome v1.2264 TRPM7 Zornitza Stark Classified gene: TRPM7 as Green List (high evidence)
Mendeliome v1.2264 TRPM7 Zornitza Stark Gene: trpm7 has been classified as Green List (High Evidence).
Mendeliome v1.2263 TRPM7 Zornitza Stark changed review comment from: Protein expressed in the distal tubule, related to TRPM6. Postulated link with hypoMg with secondary hypoCa. PMID 35561741: two families reported with dominant inheritance. F1: three affected individuals with splicing variant; some supportive functional data. F2: single affected individual, de novo missense variant. PMID 35712613: de novo missense variant in an individual with hypoMg. PMID 39099563: three affected individuals with missense variants, all de novo. Probands had DD, two had seizures.; to: Protein expressed in the distal tubule, related to TRPM6. Postulated link with hypoMg with secondary hypoCa. PMID 35561741: two families reported with dominant inheritance. F1: three affected individuals with splicing variant; some supportive functional data. F2: single affected individual, de novo missense variant. PMID 35712613: de novo missense variant in an individual with hypoMg. PMID 39099563: three affected individuals with missense variants, all de novo. Probands had DD, two had seizures.

Overall, Green for association with HypoMg.

Red for ALS and stillbirth.
Mendeliome v1.2263 TRPM7 Zornitza Stark edited their review of gene: TRPM7: Added comment: Protein expressed in the distal tubule, related to TRPM6. Postulated link with hypoMg with secondary hypoCa. PMID 35561741: two families reported with dominant inheritance. F1: three affected individuals with splicing variant; some supportive functional data. F2: single affected individual, de novo missense variant. PMID 35712613: de novo missense variant in an individual with hypoMg. PMID 39099563: three affected individuals with missense variants, all de novo. Probands had DD, two had seizures.; Changed rating: GREEN; Changed publications: 32503408, 31423533, 35561741, 35712613, 39099563; Changed phenotypes: Familial primary hypomagnesemia, MONDO:0018100, TRPM7-related, {Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to}, MIM# 105500, Cardiac arrhythmia, stillbirth
Mendeliome v1.2263 TAOK2 Zornitza Stark Phenotypes for gene: TAOK2 were changed from Generalized verrucosis; abnormal T cell activation; autism to neurodevelopmental disorder, MONDO:0700092, TAOK2-related; Generalized verrucosis; abnormal T cell activation; autism
Mendeliome v1.2262 TAOK2 Zornitza Stark Publications for gene: TAOK2 were set to 28385331; 29467497
Mendeliome v1.2261 TAOK2 Zornitza Stark Classified gene: TAOK2 as Green List (high evidence)
Mendeliome v1.2261 TAOK2 Zornitza Stark Gene: taok2 has been classified as Green List (High Evidence).
Mendeliome v1.2260 SLC13A1 Zornitza Stark Classified gene: SLC13A1 as Amber List (moderate evidence)
Mendeliome v1.2260 SLC13A1 Zornitza Stark Gene: slc13a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2259 INPP4A Chirag Patel Classified gene: INPP4A as Green List (high evidence)
Mendeliome v1.2259 INPP4A Chirag Patel Gene: inpp4a has been classified as Green List (High Evidence).
Mendeliome v1.2258 INPP4A Chirag Patel reviewed gene: INPP4A: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39315527; Phenotypes: INPP4A-related neurodevelopmental disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2258 DDX58 Zornitza Stark Marked gene: DDX58 as ready
Mendeliome v1.2258 DDX58 Zornitza Stark Added comment: Comment when marking as ready: New HGNC approved name is RIGI.
Mendeliome v1.2258 DDX58 Zornitza Stark Gene: ddx58 has been classified as Green List (High Evidence).
Mendeliome v1.2258 DDX58 Zornitza Stark Tag new gene name tag was added to gene: DDX58.
Mendeliome v1.2258 LRRC45 Zornitza Stark Marked gene: LRRC45 as ready
Mendeliome v1.2258 LRRC45 Zornitza Stark Gene: lrrc45 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2258 LRRC45 Zornitza Stark Classified gene: LRRC45 as Amber List (moderate evidence)
Mendeliome v1.2258 LRRC45 Zornitza Stark Gene: lrrc45 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2257 LRRC45 Zornitza Stark gene: LRRC45 was added
gene: LRRC45 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LRRC45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC45 were set to 39638757
Phenotypes for gene: LRRC45 were set to Neurodevelopmental disorder MONDO:0700092, LRRC45-related
Review for gene: LRRC45 was set to AMBER
Added comment: Three individuals from two families reported with two homozygous variants, one splice site and the other missense. Features of a neurological ciliopathy with some supportive experimental evidence.
Sources: Literature
Mendeliome v1.2256 WASHC3 Zornitza Stark Marked gene: WASHC3 as ready
Mendeliome v1.2256 WASHC3 Zornitza Stark Gene: washc3 has been classified as Red List (Low Evidence).
Mendeliome v1.2256 WASHC3 Zornitza Stark Phenotypes for gene: WASHC3 were changed from neurodevelopmental disorder MONDO:0700092 to neurodevelopmental disorder MONDO:0700092, WASHC3 related
Mendeliome v1.2255 WASHC3 Zornitza Stark Mode of inheritance for gene: WASHC3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2254 WASHC3 Zornitza Stark Classified gene: WASHC3 as Red List (low evidence)
Mendeliome v1.2254 WASHC3 Zornitza Stark Gene: washc3 has been classified as Red List (Low Evidence).
Mendeliome v1.2253 WASHC3 Zornitza Stark reviewed gene: WASHC3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder MONDO:0700092, WASHC3 related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2253 NAV3 Zornitza Stark Marked gene: NAV3 as ready
Mendeliome v1.2253 NAV3 Zornitza Stark Gene: nav3 has been classified as Green List (High Evidence).
Mendeliome v1.2253 NAV3 Zornitza Stark Classified gene: NAV3 as Green List (high evidence)
Mendeliome v1.2253 NAV3 Zornitza Stark Gene: nav3 has been classified as Green List (High Evidence).
Mendeliome v1.2252 NAV3 Zornitza Stark gene: NAV3 was added
gene: NAV3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NAV3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAV3 were set to 39708122; 38977784
Phenotypes for gene: NAV3 were set to Neurodevelopmental disorder, MONDO:0700092, NAV3-related
Review for gene: NAV3 was set to GREEN
Added comment: 17 individuals from 11 families reported with bi-allelic variants and neurodevelopmental phenotypes, including DD/ID and behavioural abnormalities.
Sources: Literature
Mendeliome v1.2251 EEFSEC Zornitza Stark Marked gene: EEFSEC as ready
Mendeliome v1.2251 EEFSEC Zornitza Stark Gene: eefsec has been classified as Green List (High Evidence).
Mendeliome v1.2251 EEFSEC Zornitza Stark Classified gene: EEFSEC as Green List (high evidence)
Mendeliome v1.2251 EEFSEC Zornitza Stark Gene: eefsec has been classified as Green List (High Evidence).
Mendeliome v1.2250 EEFSEC Zornitza Stark gene: EEFSEC was added
gene: EEFSEC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EEFSEC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EEFSEC were set to 39753114
Phenotypes for gene: EEFSEC were set to Neurodevelopmental disorder, MONDO:0700092, EEFSEC-related
Review for gene: EEFSEC was set to GREEN
Added comment: Nine individuals from 8 unrelated families reported with bi-allelic variants in this gene and progressive neurodevelopmental disorder manifesting with global developmental delay, progressive spasticity, ataxia, and seizures. Cerebral MRI primarily demonstrated a cerebellar pathology, including hypoplasia and progressive atrophy. In line with the clinical phenotype, an eEFSec-RNAi Drosophila model displays progressive impairment of motor function, which is reflected in the synaptic defects in this model organisms.
Sources: Literature
Mendeliome v1.2249 DAP3 Zornitza Stark Marked gene: DAP3 as ready
Mendeliome v1.2249 DAP3 Zornitza Stark Gene: dap3 has been classified as Green List (High Evidence).
Mendeliome v1.2249 DAP3 Zornitza Stark Classified gene: DAP3 as Green List (high evidence)
Mendeliome v1.2249 DAP3 Zornitza Stark Gene: dap3 has been classified as Green List (High Evidence).
Mendeliome v1.2248 DAP3 Zornitza Stark gene: DAP3 was added
gene: DAP3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DAP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DAP3 were set to 39701103
Phenotypes for gene: DAP3 were set to Mitochondrial disease MONDO:0044970, DAP3-related
Review for gene: DAP3 was set to GREEN
Added comment: DAP3 encodes the mitoribosomal small subunit 29 (MRPS29). Five unrelated individuals reported with bi-allelic variants in DAP3 and variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. Assessment of respiratory-chain function and proteomic profiling of fibroblasts from affected individuals demonstrated reduced MRPS29 protein amounts and, consequently, decreased levels of additional protein components of the mitoribosomal small subunit, as well as an associated combined deficiency of complexes I and IV. Lentiviral transduction of fibroblasts from affected individuals with wild-type DAP3 cDNA increased DAP3 mRNA expression and partially rescued protein levels of MRPS7, MRPS9, and complex I and IV subunits, demonstrating the pathogenicity of the DAP3 variants.
Sources: Literature
Mendeliome v1.2247 LRRC8C Zornitza Stark Marked gene: LRRC8C as ready
Mendeliome v1.2247 LRRC8C Zornitza Stark Gene: lrrc8c has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2247 LRRC8C Zornitza Stark Classified gene: LRRC8C as Amber List (moderate evidence)
Mendeliome v1.2247 LRRC8C Zornitza Stark Gene: lrrc8c has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2246 MYMX Chirag Patel Classified gene: MYMX as Green List (high evidence)
Mendeliome v1.2246 MYMX Chirag Patel Gene: mymx has been classified as Green List (High Evidence).
Mendeliome v1.2245 MYMX Chirag Patel reviewed gene: MYMX: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39668186; Phenotypes: congenital myopathy MONDO:0019952, congenital myopathy with facial palsy, growth restriction, and dysmorphism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2245 DDX53 Chirag Patel Classified gene: DDX53 as Green List (high evidence)
Mendeliome v1.2245 DDX53 Chirag Patel Gene: ddx53 has been classified as Green List (High Evidence).
Mendeliome v1.2244 DDX53 Chirag Patel gene: DDX53 was added
gene: DDX53 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DDX53 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DDX53 were set to PMID: 39706195
Phenotypes for gene: DDX53 were set to autism spectrum disorder MONDO:0005258
Review for gene: DDX53 was set to GREEN
Added comment: The DDX53 gene is a single-exon RNA helicase which lies intronic to PTCHD1-AS (a multi-isoform long noncoding RNA (lncRNA) at the Xp22.11 locus. It is thought to play a role in RNA decay, RNA processing, ribosome biogenesis, and translation initiation. 9 affected males and 3 affected females from 9 unrelated families with ASD and rare, predicted damaging or loss-of-function variants in DDX53 (including a gene deletion involving DDX53 and exons of the noncoding RNA PTCHD1-AS). A further 26 individuals with ASD were identified (from Autism Speaks MSSNG and Simons Foundation Autism Research Initiative) with 19 rare, damaging DDX53 variations (mostly maternally inherited). No functional evidence.
Sources: Literature
Mendeliome v1.2243 RBFOX2 Ain Roesley Phenotypes for gene: RBFOX2 were changed from Congenital heart disease MONDO:0005453, RBFOX2-related to RBFOX2-related congenital heart disorder (MONDO:0100557)
Mendeliome v1.2242 RBFOX2 Zornitza Stark Phenotypes for gene: RBFOX2 were changed from Hypoplastic left heart syndrome (HLHS) MONDO:0004933 to Congenital heart disease MONDO:0005453, RBFOX2-related
Mendeliome v1.2241 RBFOX2 Zornitza Stark Classified gene: RBFOX2 as Green List (high evidence)
Mendeliome v1.2241 RBFOX2 Zornitza Stark Gene: rbfox2 has been classified as Green List (High Evidence).
Mendeliome v1.2240 CCT3 Zornitza Stark Phenotypes for gene: CCT3 were changed from neurodevelopmental disorder MONDO:0700092, CCT3-related to Neurodevelopmental disorder with speech or visual impairment and brain hypomyelination, MIM# 621034
Mendeliome v1.2239 CCT3 Zornitza Stark reviewed gene: CCT3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with speech or visual impairment and brain hypomyelination, MIM# 621034; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2239 TCP1 Zornitza Stark Phenotypes for gene: TCP1 were changed from neurodevelopmental disorder MONDO:0700092, TCP1-related to Intellectual developmental disorder with polymicrogyria and seizures, MIM# 621021
Mendeliome v1.2238 TCP1 Zornitza Stark reviewed gene: TCP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder with polymicrogyria and seizures, MIM# 621021; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2238 TAOK2 Achchuthan Shanmugasundram reviewed gene: TAOK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 39737487; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2238 RBFOX2 Jonathon Bradshaw reviewed gene: RBFOX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26785492, 27670201, 32368696, 27485310, 25205790, 35137168, 26785492, 28991257; Phenotypes: RBFOX2-related congenital heart disorder (MONDO:0100557); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.2238 RBFOX2 Jonathon Bradshaw Deleted their review
Mendeliome v1.2238 RBFOX2 Jonathon Bradshaw changed review comment from: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (1x nonsense, 1x frameshift, 1x canonical splice variants). All 3 probands have hypoplastic left heart syndrome (HLHS) and no extra-cardiac features. Same cohort later included in PMID: 32368696, listed one additional de novo variant in this gene (missense variant) in a patient with conotruncal defects (CTDs).

- PMID: 28991257: Same research consortium as above, an additional splice variant observed in a singleton from the CHD cohort identified as a LoF predicted heterozygous mutation.

- PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492.

- PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing.

- PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS.

- PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.

- 2x NMD-predicted de novo individuals with cardiac defects have been observed (internal data).

- ClinVar: one current pathogenic entry: c.523dup (p.Ser175fs). This patient had a complex congenital cardiac defect, choreiform movement disorder, developmental delay, a clotting disorder, intermittent cyanosis, chronic lung disease, low muscle tone, short stature and failure to gain weight, mild dysmorphisms, and mild joint laxity. Brain MRI shows a stable chronic infarction, stable cerebral volume loss, and ex-vacuo prominence of ventricles (personal communication).

- ClinGen has curated this gene. Strong association and evidence supporting LoF as a mechanism of disease.; to: - PMID: 26785492: Analysed CHD (1213 congenital heart disease trios) and control (autism spectrum disorder) trios for de novo mutations. Found RBFOX2 gene had significantly more damaging de novo variants than expected: 3 de novo LoF variants (1x nonsense, 1x frameshift, 1x canonical splice variants). All 3 probands have hypoplastic left heart syndrome (HLHS) and no extra-cardiac features. Same cohort later included in PMID: 32368696, listed one additional de novo variant in this gene (missense variant) in a patient with conotruncal defects (CTDs).

- PMID: 28991257: Same research consortium as above, an additional splice variant observed in a singleton from the CHD cohort identified as a LoF predicted heterozygous mutation.

- PMID: 27670201: RNA expression study showed the silenced allele harbours a nonsense RBFOX2 variant (Arg287*), CHD patient heart tissue sample, same patient published in PMID: 26785492.

- PMID: 27485310: Functional studies using heart tissue sample from HLHS patient with NM_001031695.2:c.859C>T p.(Arg287*) showed subcellular mislocalisation, impacting its nuclear function in RNA splicing.

- PMID: 25205790: De novo 111.3kb del chr22:36038076-36149338 (hg19) which includes APOL5,APOL6,RBFOX2, in a patient with HLHS.

- PMID: 35137168: Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS.

- 2x NMD-predicted de novo individuals with cardiac defects have been observed (internal data).

- ClinVar: one current pathogenic entry: c.523dup (p.Ser175fs). This patient had a complex congenital cardiac defect, choreiform movement disorder, developmental delay, a clotting disorder, intermittent cyanosis, chronic lung disease, low muscle tone, short stature and failure to gain weight, mild dysmorphisms, and mild joint laxity. Brain MRI shows a stable chronic infarction, stable cerebral volume loss, and ex-vacuo prominence of ventricles (personal communication).

- ClinGen has curated this gene. Strong association and evidence supporting LoF as a mechanism of disease.
Mendeliome v1.2238 RBFOX2 Jonathon Bradshaw reviewed gene: RBFOX2: Rating: GREEN; Mode of pathogenicity: None; Publications: (PMID: 26785492, 27670201, 32368696, 27485310, 25205790, 35137168, 26785492, 28991257); Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.2238 EP400 Bryony Thompson Marked gene: EP400 as ready
Mendeliome v1.2238 EP400 Bryony Thompson Gene: ep400 has been classified as Green List (High Evidence).
Mendeliome v1.2238 EP400 Bryony Thompson Classified gene: EP400 as Green List (high evidence)
Mendeliome v1.2238 EP400 Bryony Thompson Gene: ep400 has been classified as Green List (High Evidence).
Mendeliome v1.2237 LRRC8C Sangavi Sivagnanasundram changed review comment from: TIMES syndrome is a multisystem disorder characterised by considerable phenotypic variability, but overlapping features include telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature. Patients exhibit striking cutis marmorata in infancy.

Two individuals from unrelated families presenting with similar features consistent with TIMES syndrome.
Leu400IlefsTer8 and Val390Leu variants were identified however the proposed mechanism of disease is GoF.
Sources: Literature; to: TIMES syndrome is a multisystem disorder characterised by considerable phenotypic variability, but overlapping features include telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature. Patients exhibit striking cutis marmorata in infancy.

Two individuals from unrelated families presenting with similar features consistent with TIMES syndrome.
Leu400IlefsTer8 and Val390Leu variants were identified however the proposed mechanism of disease is GoF.
Supporting in vitro functional assay was conducted however further evidence is required to upgrade the gene classification.
Sources: Literature
Mendeliome v1.2237 LRRC8C Sangavi Sivagnanasundram edited their review of gene: LRRC8C: Changed rating: AMBER
Mendeliome v1.2237 EP400 Sangavi Sivagnanasundram gene: EP400 was added
gene: EP400 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EP400 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EP400 were set to 39708813
Phenotypes for gene: EP400 were set to neurodevelopmental disorder with or without early-onset generalized epilepsy - MONDO:0030930
Review for gene: EP400 was set to GREEN
Added comment: 6 unrelated probands presenting with epilepsy with NDD had compound heterozygous variants in EP400. They were confirmed in trans and inherited from their asymptomatic parents.

Knockdown of EP400 ortholog in Drosophila showed an increase in seizure-like susceptibility and abnormal neurological behaviour.
Sources: Literature
Mendeliome v1.2237 LDB1 Bryony Thompson Marked gene: LDB1 as ready
Mendeliome v1.2237 LDB1 Bryony Thompson Gene: ldb1 has been classified as Green List (High Evidence).
Mendeliome v1.2237 LDB1 Bryony Thompson Classified gene: LDB1 as Green List (high evidence)
Mendeliome v1.2237 LDB1 Bryony Thompson Gene: ldb1 has been classified as Green List (High Evidence).
Mendeliome v1.2236 LDB1 Bryony Thompson gene: LDB1 was added
gene: LDB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LDB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LDB1 were set to 39680505
Phenotypes for gene: LDB1 were set to Congenital hydrocephalus MONDO:0016349
Review for gene: LDB1 was set to GREEN
Added comment: Exome-wide significant enrichment of LDB1 protein-altering de novo variants (p = 1.11 x 10-15) in a large cerebral ventriculomegaly cohort (>2,697 parent-proband trios). 8 unrelated cases with ventriculomegaly, developmental delay, and dysmorphic features with de novo variants (7 LoF variants truncate LDB1's carboxy-terminal LIM interaction domain & 1 missense).
Sources: Literature
Mendeliome v1.2235 LRRC8C Sangavi Sivagnanasundram gene: LRRC8C was added
gene: LRRC8C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LRRC8C was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LRRC8C were set to 39623139
Phenotypes for gene: LRRC8C were set to TIMES syndrome MIM#621056
Mode of pathogenicity for gene: LRRC8C was set to Other
Review for gene: LRRC8C was set to RED
Added comment: TIMES syndrome is a multisystem disorder characterised by considerable phenotypic variability, but overlapping features include telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature. Patients exhibit striking cutis marmorata in infancy.

Two individuals from unrelated families presenting with similar features consistent with TIMES syndrome.
Leu400IlefsTer8 and Val390Leu variants were identified however the proposed mechanism of disease is GoF.
Sources: Literature
Mendeliome v1.2235 WASHC3 Sangavi Sivagnanasundram gene: WASHC3 was added
gene: WASHC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WASHC3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WASHC3 were set to DOI: https://doi.org/10.1016/j.gimo.2024.101915
Phenotypes for gene: WASHC3 were set to neurodevelopmental disorder MONDO:0700092
Review for gene: WASHC3 was set to GREEN
Added comment: Three unrelated families with short stature, distinctive facies and neurodevelopmental abnormalities. Two different rare missense variants were identified between the three families (c.207A>C:p.L69F and c.1A>T, p.M1?).
In vitro functional assay was conducted on both variants showing impaired protein function supportive of disease mechanism.
Sources: Literature
Mendeliome v1.2235 SLC13A1 Sangavi Sivagnanasundram reviewed gene: SLC13A1: Rating: AMBER; Mode of pathogenicity: None; Publications: doi: https://doi.org/10.1016/j.gimo.2024.101958; Phenotypes: sulfation-related bone disorder MONDO:0019688; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2235 RICTOR Bryony Thompson Marked gene: RICTOR as ready
Mendeliome v1.2235 RICTOR Bryony Thompson Gene: rictor has been classified as Green List (High Evidence).
Mendeliome v1.2235 RICTOR Bryony Thompson Classified gene: RICTOR as Green List (high evidence)
Mendeliome v1.2235 RICTOR Bryony Thompson Gene: rictor has been classified as Green List (High Evidence).
Mendeliome v1.2234 RICTOR Bryony Thompson gene: RICTOR was added
gene: RICTOR was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RICTOR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RICTOR were set to 39738822
Phenotypes for gene: RICTOR were set to Neurodevelopmental disorder MONDO:0700092, RICTOR-related
Review for gene: RICTOR was set to GREEN
Added comment: 8 unrelated cases presenting with ID and/or developmental delay with de novo or heterozygous variants inherited from one affected parent, including three missense variants, four loss-of-function variants and one 3 kb deletion encompassing RICTOR. Possible gain of function and loss of function mechanism of disease.
Sources: Literature
Mendeliome v1.2233 UBR5 Bryony Thompson Marked gene: UBR5 as ready
Mendeliome v1.2233 UBR5 Bryony Thompson Gene: ubr5 has been classified as Green List (High Evidence).
Mendeliome v1.2233 UBR5 Bryony Thompson Classified gene: UBR5 as Green List (high evidence)
Mendeliome v1.2233 UBR5 Bryony Thompson Gene: ubr5 has been classified as Green List (High Evidence).
Mendeliome v1.2232 UBR5 Bryony Thompson gene: UBR5 was added
gene: UBR5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBR5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBR5 were set to 39721588
Phenotypes for gene: UBR5 were set to Neurodevelopmental disorder MONDO:0700092, UBR5-related
Review for gene: UBR5 was set to GREEN
Added comment: 29 individuals with a neurodevelopment syndrome (24 de novo variants) with a core phenotype characterised by developmental delay (26/28), autism (16/26), and intellectual disability (56%). Additionally, some individuals presented with epilepsy/seizures (11/27), movement disorders, and/or genital anomalies (35%). Loss of function is the expected mechanism of disease with functional experiments in C. elegans and in vitro ubiquitination assays.
Sources: Literature
Mendeliome v1.2231 MRUPAV_PLIN4 Bryony Thompson Marked STR: MRUPAV_PLIN4 as ready
Mendeliome v1.2231 MRUPAV_PLIN4 Bryony Thompson Str: mrupav_plin4 has been classified as Green List (High Evidence).
Mendeliome v1.2231 MRUPAV_PLIN4 Bryony Thompson Classified STR: MRUPAV_PLIN4 as Green List (high evidence)
Mendeliome v1.2231 MRUPAV_PLIN4 Bryony Thompson Str: mrupav_plin4 has been classified as Green List (High Evidence).
Mendeliome v1.2230 MRUPAV_PLIN4 Bryony Thompson STR: MRUPAV_PLIN4 was added
STR: MRUPAV_PLIN4 was added to Mendeliome. Sources: Literature
STR tags were added to STR: MRUPAV_PLIN4.
Mode of inheritance for STR: MRUPAV_PLIN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: MRUPAV_PLIN4 were set to 32451610; 37145156; 36151849; 35499779
Phenotypes for STR: MRUPAV_PLIN4 were set to myopathy, distal, with rimmed vacuoles MONDO:0014945
Review for STR: MRUPAV_PLIN4 was set to GREEN
STR: MRUPAV_PLIN4 was marked as clinically relevant
Added comment: Expansion of 33-mer (33 amino acids, 99 bp) identified in coding exon 3 (exon 5) of PLIN4 via linkage analysis and long read sequencing in a large Italian cohort with progressive myopathy with specific pathology including rimmed ubiquitin-positive autophagic vacuolation.
Suggested disease name myopathy with rimmed ubiquitin-positive autophagic vacuolation (MRUPAV). An additional 4 unrelated Chinese families/probands were reported. The repeat expansion is not detectable using short-read sequencing.
Normal PLIN4 alleles: 27-31 x 33-mer
Pathogenic: ≥39 x 33-mer
Sources: Literature
Mendeliome v1.2229 P2RY8 Zornitza Stark Marked gene: P2RY8 as ready
Mendeliome v1.2229 P2RY8 Zornitza Stark Gene: p2ry8 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2229 P2RY8 Zornitza Stark Classified gene: P2RY8 as Amber List (moderate evidence)
Mendeliome v1.2229 P2RY8 Zornitza Stark Gene: p2ry8 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2228 P2RY8 Zornitza Stark gene: P2RY8 was added
gene: P2RY8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: P2RY8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: P2RY8 were set to 34889940
Phenotypes for gene: P2RY8 were set to Systemic lupus erythematosus, MONDO:0007915, P2RY8-related
Review for gene: P2RY8 was set to AMBER
Added comment: One de novo variant, p.Leu257Phe, absent from gnomAD v4 identified in an individual with early-onset SLE.

Subsequent search for additional individuals in large cohorts identified:
p. Asn97Lys, inherited from mother, present in 19 individuals in gnomADv4.
p.Glu323Gly identified in 6 Chinese individuals, inheritance not determined, present in 51 individuals in gnomADv4.

Functional data support the role of the gene in immune tolerance. Role in contributing to the development of SLE is plausible, though not necessarily under a monogenic model.
Sources: Literature
Mendeliome v1.2227 PACSIN1 Zornitza Stark Marked gene: PACSIN1 as ready
Mendeliome v1.2227 PACSIN1 Zornitza Stark Gene: pacsin1 has been classified as Red List (Low Evidence).
Mendeliome v1.2227 PACSIN1 Zornitza Stark gene: PACSIN1 was added
gene: PACSIN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PACSIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PACSIN1 were set to 36622335
Phenotypes for gene: PACSIN1 were set to Systemic lupus erythematosus, MONDO:0007915, PACSIN1-related
Review for gene: PACSIN1 was set to RED
Added comment: Single individual with de novo missense variant reported, supportive functional data.
Sources: Literature
Mendeliome v1.2226 CC2D1A Zornitza Stark Phenotypes for gene: CC2D1A were changed from Autosomal recessive mental retardation, (MIM#608443) to Intellectual developmental disorder, autosomal recessive 3, MIM# 608443
Mendeliome v1.2225 CC2D1A Zornitza Stark edited their review of gene: CC2D1A: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 3, MIM# 608443
Mendeliome v1.2225 CUL4B Zornitza Stark Phenotypes for gene: CUL4B were changed from Mental retardation, X-linked, syndromic 15 (Cabezas type), MIM# 300354 to Intellectual developmental disorder, X-linked syndromic, Cabezas type, MIM#300354
Mendeliome v1.2224 CUL4B Zornitza Stark edited their review of gene: CUL4B: Changed phenotypes: Intellectual developmental disorder, X-linked syndromic, Cabezas type, MIM#300354
Mendeliome v1.2224 CRYL1 Andrew Fennell changed review comment from: About 1% of individuals with GJB2-AR NSHL are compound heterozygotes for one GJB2 pathogenic variant and one of several different deletions that include sequences upstream of GJB2 (comprising either GJB6 and portions of CRYL1 or just portions of CRYL1) that delete cis-regulatory regions of GJB2, thereby abolishing GJB2 expression. Occasionally, the deletion also includes GJB2.; to: About 1% of individuals with GJB2-AR NSHL are compound heterozygotes for one GJB2 pathogenic variant and one of several different deletions that include sequences upstream of GJB2 (comprising either GJB6 and portions of CRYL1 or just portions of CRYL1) that delete cis-regulatory regions of GJB2, thereby abolishing GJB2 expression. Occasionally, the deletion also includes GJB2.
See also PMID: 20301449 GeneReviews
Mendeliome v1.2224 CRYL1 Andrew Fennell reviewed gene: CRYL1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 30455902; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2224 WNT7A Zornitza Stark Phenotypes for gene: WNT7A were changed from Fuhrmann syndrome, MIM# 228930; Ulna and fibula, absence of, with severe limb deficiency, MIM# 276820 to Fuhrmann syndrome, MIM# 228930; Ulna and fibula, absence of, with severe limb deficiency, MIM# 276820; Santos syndrome, MIM# 613005
Mendeliome v1.2223 WNT7A Zornitza Stark Publications for gene: WNT7A were set to 21344627; 20949531; 16826533
Mendeliome v1.2222 WNT7A Zornitza Stark edited their review of gene: WNT7A: Changed publications: 19012338
Mendeliome v1.2222 WNT7A Zornitza Stark reviewed gene: WNT7A: Rating: GREEN; Mode of pathogenicity: None; Publications: 19012338]; Phenotypes: Santos syndrome, MIM# 613005; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2222 FRYL Zornitza Stark Phenotypes for gene: FRYL were changed from neurodevelopmental disorder MONDO:0700092, FRYL-related to Pan-Chung-Bellen syndrome, MIM# 621049
Mendeliome v1.2221 FRYL Zornitza Stark reviewed gene: FRYL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pan-Chung-Bellen syndrome, MIM# 621049; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2221 PIGG Ain Roesley Phenotypes for gene: PIGG were changed from Mental retardation, autosomal recessive 53, MIM#616917 to Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy MIM#616917
Mendeliome v1.2220 RFWD3 Bryony Thompson Publications for gene: RFWD3 were set to 28691929
Mendeliome v1.2219 RFWD3 Bryony Thompson Classified gene: RFWD3 as Amber List (moderate evidence)
Mendeliome v1.2219 RFWD3 Bryony Thompson Gene: rfwd3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2218 RFWD3 Bryony Thompson reviewed gene: RFWD3: Rating: AMBER; Mode of pathogenicity: None; Publications: 28691929, 38058754; Phenotypes: Fanconi anemia MONDO:0019391; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2218 GNAT1 Sangavi Sivagnanasundram reviewed gene: GNAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: inherited retinal dystrophy MONDO:0019118; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2218 ATG4A Bryony Thompson Marked gene: ATG4A as ready
Mendeliome v1.2218 ATG4A Bryony Thompson Gene: atg4a has been classified as Red List (Low Evidence).
Mendeliome v1.2218 ATG4A Bryony Thompson gene: ATG4A was added
gene: ATG4A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: ATG4A was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: ATG4A were set to 33310865
Phenotypes for gene: ATG4A were set to infectious meningitis MONDO:0004796
Review for gene: ATG4A was set to RED
Added comment: Single case with recurrent HSV2 lymphocytic Mollaret’s meningitis heterozygous for a missense variant (p.Leu90Ile).
Sources: Expert list
Mendeliome v1.2217 IFNG Bryony Thompson Publications for gene: IFNG were set to 32163377
Mendeliome v1.2216 IFNG Bryony Thompson Classified gene: IFNG as Amber List (moderate evidence)
Mendeliome v1.2216 IFNG Bryony Thompson Gene: ifng has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2215 IFNG Bryony Thompson reviewed gene: IFNG: Rating: AMBER; Mode of pathogenicity: None; Publications: 32163377, 38363432; Phenotypes: inherited susceptibility to mycobacterial diseases MONDO:0019146; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2215 TMEM173 Bryony Thompson Publications for gene: TMEM173 were set to 25401470; 25029335
Mendeliome v1.2214 TMEM173 Bryony Thompson Mode of inheritance for gene: TMEM173 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2213 TMEM173 Bryony Thompson reviewed gene: TMEM173: Rating: GREEN; Mode of pathogenicity: Other; Publications: 32673614, 36275728; Phenotypes: STING-associated vasculopathy with onset in infancy MONDO:0014405; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.2213 GTF3A Bryony Thompson Marked gene: GTF3A as ready
Mendeliome v1.2213 GTF3A Bryony Thompson Gene: gtf3a has been classified as Red List (Low Evidence).
Mendeliome v1.2213 GTF3A Bryony Thompson gene: GTF3A was added
gene: GTF3A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: GTF3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF3A were set to 36399538
Phenotypes for gene: GTF3A were set to herpes simplex encephalitis MONDO:0012521
Review for gene: GTF3A was set to RED
Added comment: A single case is reported with common variable immunodeficiency and HSE, and some supporting functional assays.
Sources: Expert list
Mendeliome v1.2212 TLR4 Bryony Thompson Phenotypes for gene: TLR4 were changed from to Inflammatory bowel disease MONDO:0005265
Mendeliome v1.2211 TLR4 Bryony Thompson Publications for gene: TLR4 were set to
Mendeliome v1.2210 TLR4 Bryony Thompson Mode of inheritance for gene: TLR4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2209 TLR4 Bryony Thompson reviewed gene: TLR4: Rating: RED; Mode of pathogenicity: None; Publications: 32042729, 31442584; Phenotypes: Inflammatory bowel disease MONDO:0005265; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2209 RNASEL Bryony Thompson Marked gene: RNASEL as ready
Mendeliome v1.2209 RNASEL Bryony Thompson Gene: rnasel has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2209 RNASEL Bryony Thompson Classified gene: RNASEL as Amber List (moderate evidence)
Mendeliome v1.2209 RNASEL Bryony Thompson Gene: rnasel has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2208 RNASEL Bryony Thompson gene: RNASEL was added
gene: RNASEL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNASEL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNASEL were set to 36538032; 9351818
Phenotypes for gene: RNASEL were set to Multisystem inflammatory syndrome, MONDO:0035375, RNASEL-related
Review for gene: RNASEL was set to AMBER
Added comment: A single case reported with a homozygous variant reported and a supporting null mouse model.
Sources: Literature
Mendeliome v1.2207 OAS1 Bryony Thompson Added comment: Comment on mode of inheritance: The monoallelic association is definitive (with a GoF mechanism of disease) and biallelic variants (LoF) have only been reported in a single family (limited evidence).
Mendeliome v1.2207 OAS1 Bryony Thompson Mode of inheritance for gene: OAS1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2206 OAS1 Bryony Thompson reviewed gene: OAS1: Rating: RED; Mode of pathogenicity: None; Publications: 36538032; Phenotypes: Multisystem inflammatory syndrome in children and adults MONDO:0035375; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2206 OTULIN Zornitza Stark Phenotypes for gene: OTULIN were changed from Services; Australian Genomics) Autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant, MIM# 621030; Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive, MIM# 617099; Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, MIM# 619986 to Autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant, MIM# 621030; Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive, MIM# 617099; Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, MIM# 619986
Mendeliome v1.2205 OTULIN Zornitza Stark Phenotypes for gene: OTULIN were changed from Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099; Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, MIM# 619986 to Services; Australian Genomics) Autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant, MIM# 621030; Autoinflammation, panniculitis, and dermatosis syndrome, autosomal recessive, MIM# 617099; Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, MIM# 619986
Mendeliome v1.2204 OTULIN Zornitza Stark edited their review of gene: OTULIN: Changed phenotypes: Autoinflammation, panniculitis, and dermatosis syndrome, autosomal dominant, MIM# 621030, Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099, Immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, MIM# 619986
Mendeliome v1.2204 RUNX1T1 Zornitza Stark Marked gene: RUNX1T1 as ready
Mendeliome v1.2204 RUNX1T1 Zornitza Stark Gene: runx1t1 has been classified as Green List (High Evidence).
Mendeliome v1.2204 RUNX1T1 Zornitza Stark Phenotypes for gene: RUNX1T1 were changed from Neurodevelopmental disorder MONDO:0700092 to Neurodevelopmental disorder MONDO:0700092, RUNX1T1-related
Mendeliome v1.2203 RUNX1T1 Zornitza Stark Publications for gene: RUNX1T1 were set to PMID: 39568205, 19172993, 22644616, 31223340
Mendeliome v1.2202 PDE12 Zornitza Stark Marked gene: PDE12 as ready
Mendeliome v1.2202 PDE12 Zornitza Stark Gene: pde12 has been classified as Green List (High Evidence).
Mendeliome v1.2202 PDE12 Zornitza Stark Phenotypes for gene: PDE12 were changed from Mitochondrial disease MONDO:0044970 to Mitochondrial disease MONDO:0044970, PDE12-related
Mendeliome v1.2201 PDE12 Chirag Patel Classified gene: PDE12 as Green List (high evidence)
Mendeliome v1.2201 PDE12 Chirag Patel Gene: pde12 has been classified as Green List (High Evidence).
Mendeliome v1.2200 CHUK Chirag Patel Classified gene: CHUK as Green List (high evidence)
Mendeliome v1.2200 CHUK Chirag Patel Gene: chuk has been classified as Green List (High Evidence).
Mendeliome v1.2199 CHUK Chirag Patel reviewed gene: CHUK: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34533979; Phenotypes: Combined immunodeficiency, MONDO:0015131, CHUK-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2199 PDE12 Chirag Patel gene: PDE12 was added
gene: PDE12 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PDE12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE12 were set to PMID: 39567835
Phenotypes for gene: PDE12 were set to Mitochondrial disease MONDO:0044970
Review for gene: PDE12 was set to GREEN
Added comment: 3 families (2 consanguineous) with 5 affected individuals with early onset mitochondrial disease presentation (3 liveborn, 2 intrauterine death).
-Family 1: 1 x infant death @3mths (no clinical information), 1 x 7yr old with neonatal respiratory and lactic acidosis, developmental delay, and mitochondrial respiratory chain deficiencies, and marked cytochrome c oxidase (COX) deficiency in muscle.
-Family 2: 1 x neonatal death @2days with metabolic acidosis and lactic acidosis, respiratory failure, lissencephaly, dysgenesis of the corpus callosum and extensive periventricular and subcortical cysts. Normal pyruvate dehydrogenase complex and electron
transfer chain activities in fibroblasts.
-Family 3: 2 x fetuses (13wks and 22wks) with increase nuchal translucency and reduced fetal movements. One had intra-uterine growth retardation, hydrops and cystic hygroma. The other had permanent flexion contractures of four limbs). Western blotting in fetal skeletal muscle showed absent respiratory chain complexes (I, IV, and V).

WES in all 3 families identified 3 different homozygous missense variants in PDE12 gene (p.Tyr155Cys, p.Gly372Glu, and p.Arg41Pro). All variants segregated with disease, were rare in gnomAD, and in silico pathogenicity prediction tools pointed towards a high likelihood of pathogenicity.

PDE12 gene encodes the poly(A)-specific exoribonuclease, involved in the quality control of mitochondrial non-coding RNAs. Patient-derived primary fibroblasts demonstrate diminished steady-state levels of PDE12 protein, whilst mitochondrial poly(A)-tail RNA sequencing revealed an accumulation of spuriously polyadenylated mitochondrial RNA, consistent with perturbed function of PDE12 protein.
Sources: Literature
Mendeliome v1.2198 RUNX1T1 Chirag Patel Classified gene: RUNX1T1 as Green List (high evidence)
Mendeliome v1.2198 RUNX1T1 Chirag Patel Gene: runx1t1 has been classified as Green List (High Evidence).
Mendeliome v1.2197 RUNX1T1 Chirag Patel gene: RUNX1T1 was added
gene: RUNX1T1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RUNX1T1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RUNX1T1 were set to PMID: 39568205, 19172993, 22644616, 31223340
Phenotypes for gene: RUNX1T1 were set to Neurodevelopmental disorder MONDO:0700092
Review for gene: RUNX1T1 was set to GREEN
Added comment: RUNX1T1 encodes a transcription regulator for hematopoietic genes and is well-known for its involvement in hematologic malignancies. Germline RUNX1T1 variants may also play a role in human congenital neurodevelopmental disorders.

PMID: 39568205
3 unrelated individuals with developmental delay, learning disability, ASD, ADHD, and dysmorphism (1 x heart defects). Trio WES identified de novo variants in RUNX1T1 gene (1 x nonsense variant in 5' region [p.Gln36Ter], 2 x missense variants in C-terminus [p.Gly412Arg and p.His521Tyr]).

PMID: 19172993
1 individual with mild-moderate ID and congenital heart disease, and chromosome t(5;8)(q32;q21.3) translocation. Molecular characterization revealed that one of the break points was within the RUNX1T1 gene. Analysis of RUNX1T1 expression in human embryonic and fetal tissues suggests a role of RUNX1T1 in brain and heart development.

PMID: 22644616
1 individual with mild ID and dysmorphism, and de novo deletion exons 3-7 in RUNX1T1.

PMID: 31223340
1 individual with ID, anaemia, atrial septal defect, dysmorphism, and seizures. Found to have a 2.1 Mb deletion at 8q21.3q22.1 involving entire RUNX1T1 gene (and 2 adjacent genes - SLC26A7 and TRIQK), and a benign familial 4.3 Mb duplication at 1p22.1p21.3 (present in unaffected healthy brother).
Sources: Literature
Mendeliome v1.2196 CAPZA2 Zornitza Stark Publications for gene: CAPZA2 were set to 32338762
Mendeliome v1.2195 CAPZA2 Zornitza Stark Classified gene: CAPZA2 as Green List (high evidence)
Mendeliome v1.2195 CAPZA2 Zornitza Stark Gene: capza2 has been classified as Green List (High Evidence).
Mendeliome v1.2194 CAPZA2 Chris Ciotta reviewed gene: CAPZA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32338762, 38374166, 35856264; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, CAPZA2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.2194 CCT6A Ain Roesley Marked gene: CCT6A as ready
Mendeliome v1.2194 CCT6A Ain Roesley Gene: cct6a has been classified as Green List (High Evidence).
Mendeliome v1.2194 CCT6A Ain Roesley Classified gene: CCT6A as Green List (high evidence)
Mendeliome v1.2194 CCT6A Ain Roesley Gene: cct6a has been classified as Green List (High Evidence).
Mendeliome v1.2193 CCT6A Ain Roesley gene: CCT6A was added
gene: CCT6A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCT6A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCT6A were set to 39480921
Phenotypes for gene: CCT6A were set to neurodevelopmental disorder MONDO:0700092, CCT6A-related
Penetrance for gene: CCT6A were set to Complete
Review for gene: CCT6A was set to GREEN
gene: CCT6A was marked as current diagnostic
Added comment: previously known as CCT6

5x individuals including 4x de novo
3x PTCS + 1x +5C>G + 1x missense

4/5 DD/ID
2/5 visual impairment
2/5 seizures
Sources: Literature
Mendeliome v1.2192 TCP1 Ain Roesley Marked gene: TCP1 as ready
Mendeliome v1.2192 TCP1 Ain Roesley Gene: tcp1 has been classified as Green List (High Evidence).
Mendeliome v1.2192 TCP1 Ain Roesley Marked gene: TCP1 as ready
Mendeliome v1.2192 TCP1 Ain Roesley Gene: tcp1 has been classified as Green List (High Evidence).
Mendeliome v1.2192 TCP1 Ain Roesley Classified gene: TCP1 as Green List (high evidence)
Mendeliome v1.2192 TCP1 Ain Roesley Gene: tcp1 has been classified as Green List (High Evidence).
Mendeliome v1.2191 TCP1 Ain Roesley gene: TCP1 was added
gene: TCP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TCP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TCP1 were set to 39480921
Phenotypes for gene: TCP1 were set to neurodevelopmental disorder MONDO:0700092, TCP1-related
Penetrance for gene: TCP1 were set to Complete
Review for gene: TCP1 was set to GREEN
gene: TCP1 was marked as current diagnostic
Added comment: previously known as CCT1

8x individuals including 5x de novo
6x PTCs + 2x missense

6/8 DD/ID
2/8 visual impairment
6/8 seizures
6/8 polymicrogyria + 1x Ventriculomegaly, white matter hyperintensities
Sources: Literature
Mendeliome v1.2190 CCT3 Ain Roesley Marked gene: CCT3 as ready
Mendeliome v1.2190 CCT3 Ain Roesley Gene: cct3 has been classified as Green List (High Evidence).
Mendeliome v1.2190 CCT3 Ain Roesley Marked gene: CCT3 as ready
Mendeliome v1.2190 CCT3 Ain Roesley Gene: cct3 has been classified as Green List (High Evidence).
Mendeliome v1.2190 CCT3 Ain Roesley Phenotypes for gene: CCT3 were changed from to neurodevelopmental disorder MONDO:0700092, CCT3-related
Mendeliome v1.2189 CCT3 Ain Roesley Classified gene: CCT3 as Green List (high evidence)
Mendeliome v1.2189 CCT3 Ain Roesley Gene: cct3 has been classified as Green List (High Evidence).
Mendeliome v1.2188 CCT3 Ain Roesley gene: CCT3 was added
gene: CCT3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCT3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCT3 were set to 39480921
Penetrance for gene: CCT3 were set to Complete
Review for gene: CCT3 was set to GREEN
gene: CCT3 was marked as current diagnostic
Added comment: 4x de novo - 3x PTCs and 1x missense

overlapping phenotypes:
4/4 ID/DD
3/4 visual impairment
2/4 seizures
4/4 Hypomyelination of white matter
Sources: Literature
Mendeliome v1.2187 CLASP1 Ain Roesley Marked gene: CLASP1 as ready
Mendeliome v1.2187 CLASP1 Ain Roesley Gene: clasp1 has been classified as Red List (Low Evidence).
Mendeliome v1.2187 CLASP1 Ain Roesley gene: CLASP1 was added
gene: CLASP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CLASP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLASP1 were set to 39040917
Phenotypes for gene: CLASP1 were set to neurodevelopmental disorder MONDO:0700092, CLASP1-related
Review for gene: CLASP1 was set to RED
gene: CLASP1 was marked as current diagnostic
Added comment: 3 siblings from a consanguineous family, homozygous for p.(Arg1481His)
at birth, all had low weight and microcephaly (< 3-4SD), profound dev delay, spasticity, seizures and lissencephaly

Arg1481His - 3 hets 0 Homs in v4
codon is highly conserved with a high REVEL score 0.83
Sources: Literature
Mendeliome v1.2186 GPATCH11 Zornitza Stark Publications for gene: GPATCH11 were set to
Mendeliome v1.2185 HMGCS1 Zornitza Stark Marked gene: HMGCS1 as ready
Mendeliome v1.2185 HMGCS1 Zornitza Stark Gene: hmgcs1 has been classified as Green List (High Evidence).
Mendeliome v1.2185 HMGCS1 Zornitza Stark Classified gene: HMGCS1 as Green List (high evidence)
Mendeliome v1.2185 HMGCS1 Zornitza Stark Gene: hmgcs1 has been classified as Green List (High Evidence).
Mendeliome v1.2184 HMGCS1 Zornitza Stark gene: HMGCS1 was added
gene: HMGCS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HMGCS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HMGCS1 were set to 39531736
Phenotypes for gene: HMGCS1 were set to Rigid spine syndrome, MONDO:0019951, HMGCS1-related
Review for gene: HMGCS1 was set to GREEN
Added comment: Five individuals from four families reported. All individuals presented with spinal rigidity primarily affecting the cervical and dorsolumbar regions, scoliosis, and respiratory insufficiency. Creatine kinase levels were variably elevated. The clinical course worsened with intercurrent disease or certain drugs in some; one individual died from respiratory failure following infection. Muscle biopsies revealed irregularities in oxidative enzyme staining with occasional internal nuclei and rimmed vacuoles.
HMGCS1 encodes a critical enzyme of the mevalonate pathway. Notably, biallelic hypomorphic variants in downstream enzymes including HMGCR and GGPS1 are associated with muscular dystrophy. Hmgcs1 mutant zebrafish displayed severe early defects, including immobility at 2 days and death by day 3 post-fertilisation and were rescued by HMGCS1 mRNA. Four variants tested (S447P, Q29L M70T, and C268S) have reduced function compared to wildtype HMGCS1 in zebrafish rescue assays
Sources: Literature
Mendeliome v1.2183 CMPK2 Zornitza Stark Marked gene: CMPK2 as ready
Mendeliome v1.2183 CMPK2 Zornitza Stark Gene: cmpk2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2183 CMPK2 Zornitza Stark Classified gene: CMPK2 as Amber List (moderate evidence)
Mendeliome v1.2183 CMPK2 Zornitza Stark Gene: cmpk2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2182 CMPK2 Zornitza Stark gene: CMPK2 was added
gene: CMPK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CMPK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CMPK2 were set to 36443312
Phenotypes for gene: CMPK2 were set to bilateral striopallidodentate calcinosis, MONDO:0008947, CMPK2-related
Review for gene: CMPK2 was set to AMBER
Added comment: Three individuals from two unrelated families reported. One family (two sibs) with homozygous start loss variant, and the other family with compound het variants. Adult-onset neurodegenerative disorder. Extensive functional data including mouse model. Evidence of underlying mitochondrial dysfunction.
Sources: Literature
Mendeliome v1.2181 MAP3K3 Zornitza Stark Phenotypes for gene: MAP3K3 were changed from Cerebral malformation, MONDO:0016054, MAP3K3-related to Cerebral cavernous malformations 5, MIM# 621032
Mendeliome v1.2180 MAP3K3 Zornitza Stark edited their review of gene: MAP3K3: Changed phenotypes: Cerebral cavernous malformations 5, MIM# 621032
Mendeliome v1.2180 POLA2 Bryony Thompson Phenotypes for gene: POLA2 were changed from Telomere biology disorders; Coats plus syndrome MONDO:0012815 to Telomere biology syndrome MONDO:0100137
Mendeliome v1.2179 POLA2 Bryony Thompson Marked gene: POLA2 as ready
Mendeliome v1.2179 POLA2 Bryony Thompson Gene: pola2 has been classified as Green List (High Evidence).
Mendeliome v1.2179 POLA2 Bryony Thompson Classified gene: POLA2 as Green List (high evidence)
Mendeliome v1.2179 POLA2 Bryony Thompson Gene: pola2 has been classified as Green List (High Evidence).
Mendeliome v1.2178 CTGF Bryony Thompson Marked gene: CTGF as ready
Mendeliome v1.2178 CTGF Bryony Thompson Gene: ctgf has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2178 CTGF Bryony Thompson Phenotypes for gene: CTGF were changed from Kyphomelic dysplasia to Kyphomelic dysplasia MONDO:0008881; Spondyloepimetaphyseal dysplasia MONDO:0100510
Mendeliome v1.2177 CTGF Bryony Thompson Publications for gene: CTGF were set to 39506047
Mendeliome v1.2176 CTGF Bryony Thompson Classified gene: CTGF as Amber List (moderate evidence)
Mendeliome v1.2176 CTGF Bryony Thompson Gene: ctgf has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2175 CTGF Bryony Thompson edited their review of gene: CTGF: Changed publications: 39414788, 20534727
Mendeliome v1.2175 CTGF Bryony Thompson edited their review of gene: CTGF: Changed publications: 39414788, 39414788
Mendeliome v1.2175 CTGF Bryony Thompson reviewed gene: CTGF: Rating: RED; Mode of pathogenicity: None; Publications: 39414788; Phenotypes: Spondyloepimetaphyseal dysplasia MONDO:0100510; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2175 GUK1 Bryony Thompson Phenotypes for gene: GUK1 were changed from Mitochondrial DNA depletion syndrome MONDO:0018158 to Mitochondrial DNA depletion syndrome MONDO:0018158, GUK1-related
Mendeliome v1.2174 GUK1 Bryony Thompson Marked gene: GUK1 as ready
Mendeliome v1.2174 GUK1 Bryony Thompson Gene: guk1 has been classified as Green List (High Evidence).
Mendeliome v1.2174 GUK1 Bryony Thompson Classified gene: GUK1 as Green List (high evidence)
Mendeliome v1.2174 GUK1 Bryony Thompson Gene: guk1 has been classified as Green List (High Evidence).
Mendeliome v1.2173 GUK1 Bryony Thompson gene: GUK1 was added
gene: GUK1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GUK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GUK1 were set to 39230499
Phenotypes for gene: GUK1 were set to Mitochondrial DNA depletion syndrome MONDO:0018158
Review for gene: GUK1 was set to GREEN
Added comment: 4 adult cases from 3 unrelated families with biallelic variants leading to GUK1 deficiency. Cases presented with ptosis, ophthalmoparesis, myopathic proximal limb weakness, variable hepatopathy, and altered T-lymphocyte profiles. Initial manifestations in childhood or adolescence and developed ptosis and skeletal myopathy. mtDNA depletion/deletions are present in muscle biopsies of reduced activities of mitochondrial respiratory chain enzymes in all 4 cases.
Sources: Literature
Mendeliome v1.2172 PPP2R2B Bryony Thompson Phenotypes for gene: PPP2R2B were changed from to Neurodevelopmental disorder MONDO:0700092, PPP2R2B-related
Mendeliome v1.2171 PPP2R2B Bryony Thompson Publications for gene: PPP2R2B were set to
Mendeliome v1.2170 PPP2R2B Bryony Thompson Mode of inheritance for gene: PPP2R2B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2169 PPP2R2B Bryony Thompson Classified gene: PPP2R2B as Amber List (moderate evidence)
Mendeliome v1.2169 PPP2R2B Bryony Thompson Gene: ppp2r2b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2168 PPP2R2B Bryony Thompson reviewed gene: PPP2R2B: Rating: AMBER; Mode of pathogenicity: None; Publications: 25356899, 39565297; Phenotypes: Neurodevelopmental disorder MONDO:0700092, PPP2R2B-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2168 PPP2R2B Bryony Thompson Deleted their review
Mendeliome v1.2168 PPP2R2B Bryony Thompson Deleted their comment
Mendeliome v1.2168 PPP2R2B Bryony Thompson edited their review of gene: PPP2R2B: Added comment: 5 cases with NDD and heterozygous missense (4/5 confirmed de novo): p.Thr246Lys (unknown inheritance), p.Asn310Lys (confirmed de novo), p.Glu37Lys (confirmed de novo, also had RNU4-2 path de novo Path variant), p.Ile427Thr (confirmed de novo, also had TAOK1 inherited Path variant), p.Arg149Pro (confirmed de novo). 5/5 with intellectual disability and developmental delay, 4/5 with seizures, 2/5 with hearing loss/auditory neuropathy. Study includes in vitro functional assays supporting a possible loss of function mechanism of disease. The 2 missense with additional diagnoses (E37K & I427T) demonstrated a partial reduction in PP2A holoenzyme assembly. Only 3 cases with a possible diagnosis that could be attributed to the PPP2R2B only, and only 2 were confirmed de novo.; Changed rating: AMBER; Changed publications: 25356899, 39565297; Changed phenotypes: Neurodevelopmental disorder MONDO:0700092
Mendeliome v1.2168 PPP2R2B Bryony Thompson Deleted their comment
Mendeliome v1.2168 GPATCH11 Sangavi Sivagnanasundram edited their review of gene: GPATCH11: Changed phenotypes: early-onset retinal dystrophy with neurological impairment MONDO:0019118
Mendeliome v1.2168 CTGF Sangavi Sivagnanasundram edited their review of gene: CTGF: Changed phenotypes: Kyphomelic dysplasia, skeletal dysplasia MONDO:0018230
Mendeliome v1.2168 WDR47 Bryony Thompson Marked gene: WDR47 as ready
Mendeliome v1.2168 WDR47 Bryony Thompson Gene: wdr47 has been classified as Green List (High Evidence).
Mendeliome v1.2168 WDR47 Bryony Thompson Classified gene: WDR47 as Green List (high evidence)
Mendeliome v1.2168 WDR47 Bryony Thompson Gene: wdr47 has been classified as Green List (High Evidence).
Mendeliome v1.2167 WDR47 Bryony Thompson gene: WDR47 was added
gene: WDR47 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WDR47 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR47 were set to 39609633; 35474353
Phenotypes for gene: WDR47 were set to Complex neurodevelopmental disorder MONDO:0100038, WDR47-related; Congenital heart disease MONDO:0005453
Review for gene: WDR47 was set to GREEN
Added comment: PMID: 39609633 - 7 cases from 5 unrelated families with biallelic variants and a complex neurodevelopmental syndrome. The most frequent phenotypes were corpus callosum dysgenesis (7/7), microcephaly (7/7), mild to severe intellectual disability (7/7), epilepsy (7/7). Additionally, mouse models recapitulate the human phenotype. Loss of function is the mechanism of disease. Heterozygous parents had no phenotype.

Limited evidence for mono allelic association with congenital heart defects
PMID: 35474353 - rare assumed de novo heterozygous variant (NM_014969.5:c.2056G>A p.(Val686Ile) - 10 hets in gnomAD v4.1) detected in a case with heterotaxy including AVCD, vena azygos continuation, artery lusoria, truncus bicaroticus and polysplenia. Screening of exams for 2,019 individuals with situs inversus totalis, heterotaxy, or isolated CHD detected 2 additional individuals with monoallelic rare missense variants. No functional assays or other supporting evidence. All variants are VUS
Sources: Literature
Mendeliome v1.2166 CTGF Sangavi Sivagnanasundram changed review comment from: CCN2 is the new HGNC approved name.

PMID: 39506047
Three individuals from two unrelated consanguineous families presented with short stature, facial dysmorphism and kyphomelic skeletal dysplasia.

A rare missense variant in family 1 (Cys148Tyr) and novel frameshift variant (Pro260LeufsTer7) in family 2 was identified in homozygous state.
Zebrafish model was also conducted that showed altered body curvature and impaired cartilage formation in craniofacial region resulting in either bent of missing tails.

A missense variant c.443G>A; p.(Cys148Tyr) in exon 3 and a frameshift variant, c.779_786del; p.(Pro260LeufsTer7) in exon 5.
Sources: Literature; to: CCN2 is the new HGNC approved name.

PMID: 39506047
Three individuals from two unrelated consanguineous families presented with short stature, facial dysmorphism and kyphomelic skeletal dysplasia.

A rare missense variant in family 1 (Cys148Tyr) and novel frameshift variant (Pro260LeufsTer7) in family 2 was identified in homozygous state.
Zebrafish model was also conducted that showed altered body curvature and impaired cartilage formation in craniofacial region resulting in either bent or missing tails.

A missense variant c.443G>A; p.(Cys148Tyr) in exon 3 and a frameshift variant, c.779_786del; p.(Pro260LeufsTer7) in exon 5.
Sources: Literature
Mendeliome v1.2166 CTGF Sangavi Sivagnanasundram gene: CTGF was added
gene: CTGF was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CTGF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTGF were set to 39506047
Phenotypes for gene: CTGF were set to Kyphomelic dysplasia
Review for gene: CTGF was set to AMBER
Added comment: CCN2 is the new HGNC approved name.

PMID: 39506047
Three individuals from two unrelated consanguineous families presented with short stature, facial dysmorphism and kyphomelic skeletal dysplasia.

A rare missense variant in family 1 (Cys148Tyr) and novel frameshift variant (Pro260LeufsTer7) in family 2 was identified in homozygous state.
Zebrafish model was also conducted that showed altered body curvature and impaired cartilage formation in craniofacial region resulting in either bent of missing tails.

A missense variant c.443G>A; p.(Cys148Tyr) in exon 3 and a frameshift variant, c.779_786del; p.(Pro260LeufsTer7) in exon 5.
Sources: Literature
Mendeliome v1.2166 GPATCH11 Sangavi Sivagnanasundram reviewed gene: GPATCH11: Rating: GREEN; Mode of pathogenicity: None; Publications: 39572588; Phenotypes: early-onset retinal dystrophy with neurological impairment; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2166 POLA2 Sangavi Sivagnanasundram gene: POLA2 was added
gene: POLA2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: POLA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLA2 were set to 39616267
Phenotypes for gene: POLA2 were set to Telomere biology disorders; Coats plus syndrome MONDO:0012815
Review for gene: POLA2 was set to GREEN
Added comment: New gene-disease association.

PMID: 39616267 - Five individuals from two unrelated swedish families presenting with clinical phenotype suggestive of a TBD disorder with Coats plus features including retinal and gastrointestinal telangiectasias. Affected individuals also presented with shortened telomeres.

Compound heterozygous variants were identified in both families.
Family A (Ile96Thr;Pro424Leu) - Both variants are present in gnomAD v4.1 but FAF is rare enough for AR condition [c.287 T > C, p.(Ile96Thr) - FAF 0.002%; c.1271 C > T, p.(Pro424Leu) - FAF 0.0002 %]
Family B (Ile96Thr; intragenic SNV resulting in the deletion of the 5’ terminal and exon 1) - same missense as the other family along with an SNV.

In vitro assay using CRISPR/Cas9 genome engineering into HEK293T to assess whether the p.(Ile96Thr) would affect telomere length. The subclones carrying the missense variant showed telomeric shortening of ~4kb compared to the WT subclones.
Sources: Literature
Mendeliome v1.2166 FGF8 Zornitza Stark edited their review of gene: FGF8: Added comment: Association with CHD: Two individuals reported but extensive functional data. MODERATE by ClinGen.; Changed publications: 32664970, 7768185, 32664970, 10603341, 19509466, 9462741, 10603341, 12223415; Changed phenotypes: Hypogonadotropic hypogonadism 6 with or without anosmia, MIM# 612702, Hypoplastic femurs and pelvis, MIM#619545, Congenital heart disease MONDO:0005453, FGF8-related
Mendeliome v1.2166 ROCK2 Bryony Thompson Marked gene: ROCK2 as ready
Mendeliome v1.2166 ROCK2 Bryony Thompson Gene: rock2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2166 ROCK2 Bryony Thompson Classified gene: ROCK2 as Amber List (moderate evidence)
Mendeliome v1.2166 ROCK2 Bryony Thompson Gene: rock2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2165 PPP5C Bryony Thompson Marked gene: PPP5C as ready
Mendeliome v1.2165 PPP5C Bryony Thompson Gene: ppp5c has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2165 PPP5C Bryony Thompson Classified gene: PPP5C as Amber List (moderate evidence)
Mendeliome v1.2165 PPP5C Bryony Thompson Gene: ppp5c has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2164 RAB35 Bryony Thompson changed review comment from: PMID: 38432637 - a single case with a neurodevelopmental disorder and a homozygous missense variant (c.80G>A; p.R27H) and supporting in vitro functional assays.
PMID: 36928819 - Posterior probability association (PPA) 0.955 for familial hypercholesterolaemia under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 469 FH cases and 55,033 controls used in BeviMed analysis. A nonsense variant and frameshift enriched in the FH cohort (n=6).
Sources: Literature; to: PMID: 38432637 - a single case with a neurodevelopmental disorder and a homozygous missense variant (c.80G>A; p.R27H) and supporting in vitro functional assays.
PMID: 36928819 - Posterior probability association (PPA) 0.955 for familial hypercholesterolaemia under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 469 FH cases and 55,033 controls used in BeviMed analysis. A nonsense variant and frameshift enriched in the FH cohort (n=6). Cosegergation in 1 affected relative also reported.
Sources: Literature
Mendeliome v1.2164 RAB35 Bryony Thompson Marked gene: RAB35 as ready
Mendeliome v1.2164 RAB35 Bryony Thompson Gene: rab35 has been classified as Red List (Low Evidence).
Mendeliome v1.2164 RAB35 Bryony Thompson gene: RAB35 was added
gene: RAB35 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB35 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: RAB35 were set to 38432637; 36928819
Phenotypes for gene: RAB35 were set to familial hypercholesterolemia MONDO:0005439; neurodevelopmental disorder MONDO:0700092
Review for gene: RAB35 was set to RED
Added comment: PMID: 38432637 - a single case with a neurodevelopmental disorder and a homozygous missense variant (c.80G>A; p.R27H) and supporting in vitro functional assays.
PMID: 36928819 - Posterior probability association (PPA) 0.955 for familial hypercholesterolaemia under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 469 FH cases and 55,033 controls used in BeviMed analysis. A nonsense variant and frameshift enriched in the FH cohort (n=6).
Sources: Literature
Mendeliome v1.2163 ARPC3 Bryony Thompson Marked gene: ARPC3 as ready
Mendeliome v1.2163 ARPC3 Bryony Thompson Gene: arpc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2163 ARPC3 Bryony Thompson Classified gene: ARPC3 as Amber List (moderate evidence)
Mendeliome v1.2163 ARPC3 Bryony Thompson Gene: arpc3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2162 ARPC3 Bryony Thompson gene: ARPC3 was added
gene: ARPC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ARPC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARPC3 were set to 36928819; 26166300
Phenotypes for gene: ARPC3 were set to Charcot-Marie-Tooth disease MONDO:0015626
Review for gene: ARPC3 was set to AMBER
Added comment: Posterior probability association (PPA) 0.995 for Charcot-Marie Tooth disease under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 549 CMT cases and 54,856 controls used in BeviMed analysis. 5 rare variants (missense, splice region, a splice acceptor site) enriched in the CMT cohort (n=14).
Additionally, ArpC3 conditional knockout mice fail to ensheath axons causing axon dysfunction.
Sources: Literature
Mendeliome v1.2161 USP33 Bryony Thompson changed review comment from: Posterior probability association (PPA) 0.977 for extreme early-onset hypertension under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 2 splice site variants enriched in a renal and urinary tract disorders cohort (n=6).
Sources: Literature; to: Posterior probability association (PPA) 0.977 for extreme early-onset hypertension under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 182 early-onset hypertension cases and 55,305 controls used in BeviMed analysis. 2 splice site variants enriched in a renal and urinary tract disorders cohort (n=6).
Sources: Literature
Mendeliome v1.2161 FMN1 Bryony Thompson changed review comment from: PMID: 36928819 - Posterior probability association (PPA) between 0.95-0.96 for congenital hearing impairment under a recessive MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. A splice variant (n=3) & frameshift variant (n=1), possibly in 2 cases and possibly in trans (cosegregation in 2 unaffected relatives mentioned); to: PMID: 36928819 - Posterior probability association (PPA) between 0.95-0.96 for congenital hearing impairment under a recessive MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 510 CHI cases assessed and 54,738 controls in BeviMed analysis. A splice variant (n=3) & frameshift variant (n=1), possibly in 2 cases and possibly in trans (cosegregation in 2 unaffected relatives mentioned)
Mendeliome v1.2161 USP33 Bryony Thompson Classified gene: USP33 as Red List (low evidence)
Mendeliome v1.2161 USP33 Bryony Thompson Gene: usp33 has been classified as Red List (Low Evidence).
Mendeliome v1.2160 USP33 Bryony Thompson Marked gene: USP33 as ready
Mendeliome v1.2160 USP33 Bryony Thompson Gene: usp33 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2160 USP33 Bryony Thompson Classified gene: USP33 as Amber List (moderate evidence)
Mendeliome v1.2160 USP33 Bryony Thompson Gene: usp33 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2159 USP33 Bryony Thompson gene: USP33 was added
gene: USP33 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: USP33 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: USP33 were set to 36928819
Phenotypes for gene: USP33 were set to Renal hypertension MONDO:0001105
Review for gene: USP33 was set to AMBER
Added comment: Posterior probability association (PPA) 0.977 for extreme early-onset hypertension under a dominant MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. 2 splice site variants enriched in a renal and urinary tract disorders cohort (n=6).
Sources: Literature
Mendeliome v1.2158 UCHL1 Bryony Thompson Marked gene: UCHL1 as ready
Mendeliome v1.2158 UCHL1 Bryony Thompson Gene: uchl1 has been classified as Green List (High Evidence).
Mendeliome v1.2158 UCHL1 Bryony Thompson Classified gene: UCHL1 as Green List (high evidence)
Mendeliome v1.2158 UCHL1 Bryony Thompson Gene: uchl1 has been classified as Green List (High Evidence).
Mendeliome v1.2157 UCHL1 Bryony Thompson reviewed gene: UCHL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23359680, 3340629, 28007905, 32656641, 29735986, 28007905, 35986737, 39030458; Phenotypes: Spastic paraplegia 79A, autosomal dominant, MIM# 620221, Spastic paraplegia 79, autosomal recessive, 615491, MONDO:0014209, Neurodegenerative disease, MONDO:0005559, UCHL1-related; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.2157 UCHL1 Bryony Thompson gene: UCHL1 was added
gene: UCHL1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: UCHL1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: UCHL1 were set to 23359680; 3340629; 28007905; 32656641; 29735986; 28007905; 35986737; 39030458
Phenotypes for gene: UCHL1 were set to Spastic paraplegia 79A, autosomal dominant, MIM# 620221; Spastic paraplegia 79, autosomal recessive, 615491; MONDO:0014209; Neurodegenerative disease, MONDO:0005559, UCHL1-related
Mendeliome v1.2156 FMN1 Bryony Thompson Publications for gene: FMN1 were set to 20610440; 19383632; 15202026
Mendeliome v1.2155 FMN1 Bryony Thompson Phenotypes for gene: FMN1 were changed from oligosyndactyly; radioulnar synostosis; hearing loss; renal defects to Hearing loss disorder MONDO:0005365
Mendeliome v1.2154 FMN1 Bryony Thompson edited their review of gene: FMN1: Added comment: PMID: 36928819 - Posterior probability association (PPA) between 0.95-0.96 for congenital hearing impairment under a recessive MOI in the 100,000 Genomes project “Rareservoir” using a Bayesian statistical method - BeviMed. A splice variant (n=3) & frameshift variant (n=1), possibly in 2 cases and possibly in trans (cosegregation in 2 unaffected relatives mentioned); Changed publications: 20610440, 19383632, 15202026, 36928819; Changed phenotypes: Hearing loss disorder MONDO:0005365
Mendeliome v1.2154 PPP5C Lucy Spencer gene: PPP5C was added
gene: PPP5C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPP5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP5C were set to 35361529; 25363768; 33057194
Phenotypes for gene: PPP5C were set to Neurodevelopmental disorder, MONDO:0700092, PPP5C-related
Review for gene: PPP5C was set to AMBER
Added comment: PMID: 35361529 - reported a de novo missense in a proband with microcephaly, developmental delay and epilepsy. However, after personal communication with the undiagnosed disease network this proband has since been found to have a different diagnosis with a nonsense and a missense in VARS1 identified, so unclear if the PPP5C variant is contributing to their phenotype.

3 more probands with de novo missense variants have been published in large autism or developmental disorder cohort with limited information (PMIDs: 25363768, 33057194)

An internal VCGS proband with intellectual disability and failure to thrive was also found to have a de novo missense variant in this gene.
Sources: Literature
Mendeliome v1.2154 MRVI1 Bryony Thompson Marked gene: MRVI1 as ready
Mendeliome v1.2154 MRVI1 Bryony Thompson Gene: mrvi1 has been classified as Red List (Low Evidence).
Mendeliome v1.2154 MRVI1 Bryony Thompson Phenotypes for gene: MRVI1 were changed from moyamoya syndrome to Moyamoya disease MONDO:0016820
Mendeliome v1.2153 MRVI1 Bryony Thompson edited their review of gene: MRVI1: Changed phenotypes: Moyamoya disease MONDO:0016820
Mendeliome v1.2153 MRVI1 Bryony Thompson gene: MRVI1 was added
gene: MRVI1 was added to Mendeliome. Sources: NHS GMS
new gene name tags were added to gene: MRVI1.
Mode of inheritance for gene: MRVI1 was set to Unknown
Publications for gene: MRVI1 were set to 30001348
Phenotypes for gene: MRVI1 were set to moyamoya syndrome
Review for gene: MRVI1 was set to RED
Added comment: A single report of a variant as a possible modifier of NF1-related Moyamoya disease. The SNP rs35857561 segregates co-occurring with NF1 in 2 families and Moyamoya disease. rs35857561 is a common SNP and IRAG1 (new gene name) hasn't been reported in association with Mendelian disease.
Sources: NHS GMS
Mendeliome v1.2152 DHDDS Zornitza Stark Publications for gene: DHDDS were set to 27343064; 29100083; 21295283; 34382076
Mendeliome v1.2151 DHDDS Zornitza Stark edited their review of gene: DHDDS: Added comment: Bi-allelic variants: ClinGen have lumped the CDG together with the RP -- likely represent a continuum of severity rather than distinct disorders.; Changed publications: 27343064, 29100083, 21295283, 27343064, 21295283, 28130426, 29276052, 32483926, 36046393, 24078709, 28005406, 36046393
Mendeliome v1.2151 SLC35F1 Lucy Spencer changed review comment from: Probable 2nd internal VCGS case 24W004707 with intellectual disability and seizures and a de novo Gly226Arg variant.; to: Probable 2nd internal VCGS case with intellectual disability and seizures and a de novo Gly226Arg variant.
Mendeliome v1.2151 WDR83OS Zornitza Stark Phenotypes for gene: WDR83OS were changed from complex neurodevelopmental disorder MONDO:0100038; neurodevelopmental disorder with hypercholanemia to Neurodevelopmental disorder with variable familial hypercholanemia, MIM# 621016
Mendeliome v1.2150 GARS Zornitza Stark Phenotypes for gene: GARS were changed from Spinal muscular atrophy, infantile, James type, MIM# 619042; Charcot-Marie-Tooth disease, type 2D, MIM# 601472; Neuronopathy, distal hereditary motor, type VA, MIM# 600794; Multi-system mitochondrial disorder to Mitochondrial disease (MONDO:0044970), GARS1-related; Spinal muscular atrophy, infantile, James type, MIM# 619042; Charcot-Marie-Tooth disease, type 2D, MIM# 601472; Neuronopathy, distal hereditary motor, type VA, MIM# 600794; Multi-system mitochondrial disorder
Mendeliome v1.2149 GARS Zornitza Stark edited their review of gene: GARS: Changed phenotypes: Mitochondrial disease (MONDO:0044970), GARS1-related, Spinal muscular atrophy, infantile, James type, MIM# 619042, Charcot-Marie-Tooth disease, type 2D, MIM# 601472, Neuronopathy, distal hereditary motor, type VA, MIM# 600794, Multi-system mitochondrial disorder
Mendeliome v1.2149 SLC35F1 Zornitza Stark Classified gene: SLC35F1 as Amber List (moderate evidence)
Mendeliome v1.2149 SLC35F1 Zornitza Stark Gene: slc35f1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2148 SLC35F1 Lucy Spencer reviewed gene: SLC35F1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, SLC35F1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.2148 LINC01578 Zornitza Stark Phenotypes for gene: LINC01578 were changed from Neurodevelopmental disorder, MONDO:0700092, CHASERR-related to Neurodevelopmental disorder with dysmorphic facies, absent speech and ambulation, and brain abnormalities, MIM# 621012
Mendeliome v1.2147 LINC01578 Zornitza Stark edited their review of gene: LINC01578: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies, absent speech and ambulation, and brain abnormalities, MIM# 621012
Mendeliome v1.2147 ATP5A1 Lucy Spencer reviewed gene: ATP5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 34483339, 34954817, 23599390, 23596069; Phenotypes: Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MIM#620358), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2147 NFATC2 Bryony Thompson Classified gene: NFATC2 as Amber List (moderate evidence)
Mendeliome v1.2147 NFATC2 Bryony Thompson Gene: nfatc2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2146 NFATC2 Bryony Thompson reviewed gene: NFATC2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35789258, 38427060; Phenotypes: Lymphoproliferative syndrome, MONDO:0016537, NFATC2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2146 MED12L Zornitza Stark Phenotypes for gene: MED12L were changed from Intellectual disability; Seizures; Autism to Neurodevelopmental disorder, MONDO:0700092, MED12L-related; Intellectual disability; Seizures; Autism
Mendeliome v1.2145 MED12L Zornitza Stark edited their review of gene: MED12L: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, MED12L-related, Intellectual disability, Seizures, Autism
Mendeliome v1.2145 RFC4 Zornitza Stark Marked gene: RFC4 as ready
Mendeliome v1.2145 RFC4 Zornitza Stark Gene: rfc4 has been classified as Green List (High Evidence).
Mendeliome v1.2145 RFC4 Zornitza Stark Phenotypes for gene: RFC4 were changed from RFC4-related multisystem disorder to Morimoto-Ryu-Malicdan neuromuscular syndrome, MIM# 621010
Mendeliome v1.2144 DHRSX Zornitza Stark Phenotypes for gene: DHRSX were changed from congenital disorder of glycosylation, MONDO:0015286 to Congenital disorder of glycosylation, type 1DD, MIM# 301133
Mendeliome v1.2143 PDCD1 Zornitza Stark Phenotypes for gene: PDCD1 were changed from PDCD1 deficiency; Inborn errors of immunity, MONDO:0003778 to Autoimmune disease with susceptibility to mycobacterium tuberculosis, MIM# 621004
Mendeliome v1.2142 POMT1 Ain Roesley Phenotypes for gene: POMT1 were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1 236670; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 1 613155; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 609308 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 1 236670; Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 1 613155; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 1 609308
Mendeliome v1.2141 SH3KBP1 Bryony Thompson Classified gene: SH3KBP1 as Amber List (moderate evidence)
Mendeliome v1.2141 SH3KBP1 Bryony Thompson Gene: sh3kbp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2140 SH3KBP1 Bryony Thompson edited their review of gene: SH3KBP1: Changed phenotypes: immunodeficiency 61 MONDO:0010296
Mendeliome v1.2140 SH3KBP1 Bryony Thompson reviewed gene: SH3KBP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 29636373, 21708930; Phenotypes: Immunodeficiency, common variable, 4 MONDO:0013284; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2140 RFC1 Bryony Thompson Publications for gene: RFC1 were set to 30926972; 33103729; 35883251
Mendeliome v1.2139 RFC1 Bryony Thompson Classified gene: RFC1 as Green List (high evidence)
Mendeliome v1.2139 RFC1 Bryony Thompson Gene: rfc1 has been classified as Green List (High Evidence).
Mendeliome v1.2138 ANAPC1 Zornitza Stark Tag founder tag was added to gene: ANAPC1.
Mendeliome v1.2138 WASHC5 Zornitza Stark Mode of inheritance for gene: WASHC5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2137 WASHC5 Zornitza Stark edited their review of gene: WASHC5: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2137 ZCCHC8 Zornitza Stark Classified gene: ZCCHC8 as Green List (high evidence)
Mendeliome v1.2137 ZCCHC8 Zornitza Stark Gene: zcchc8 has been classified as Green List (High Evidence).
Mendeliome v1.2136 ZCCHC8 Zornitza Stark reviewed gene: ZCCHC8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: pulmonary fibrosis and/or bone marrow failure, telomere-related, 5 MONDO:0032865; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2136 RTTN Zornitza Stark Phenotypes for gene: RTTN were changed from Microcephaly, short stature, and polymicrogyria with seizures, MIM# 614833; Intellectual disability; cerebral polymicrogyria; primary microcephaly; growth defects; congenital anomalies to Microcephaly, short stature, and polymicrogyria with seizures, MIM# 614833; microcephalic primordial dwarfism due to RTTN deficiency MONDO:0018764
Mendeliome v1.2135 PLA2G4A Sangavi Sivagnanasundram reviewed gene: PLA2G4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 18451993, 23268370, 25102815; Phenotypes: cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder MONDO:0018794; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 RTTN Sangavi Sivagnanasundram reviewed gene: RTTN: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008471; Phenotypes: microcephalic primordial dwarfism due to RTTN deficiency MONDO:0018764; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 ZCCHC8 Sangavi Sivagnanasundram reviewed gene: ZCCHC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 31488579, 38375433; Phenotypes: pulmonary fibrosis and/or bone marrow failure, telomere-related, 5 MONDO:0032865; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2135 SLC18A2 Sangavi Sivagnanasundram reviewed gene: SLC18A2: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008459; Phenotypes: brain dopamine-serotonin vesicular transport disease MONDO:0018130; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 RFC1 Sangavi Sivagnanasundram reviewed gene: RFC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35883251, 36478048, 36289003; Phenotypes: cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome MONDO:0044720; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 IQCB1 Sangavi Sivagnanasundram reviewed gene: IQCB1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008440; Phenotypes: ciliopathy MONDO:0005308; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 WASHC5 Sangavi Sivagnanasundram reviewed gene: WASHC5: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:006537, https://search.clinicalgenome.org/CCID:006538; Phenotypes: hereditary spastic paraplegia 8 MONDO:0011339, Ritscher-Schinzel syndrome 1 MONDO:0009073; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2135 G6PC Sangavi Sivagnanasundram reviewed gene: G6PC: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008420; Phenotypes: glycogen storage disease I MONDO:0002413; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 PYGL Sangavi Sivagnanasundram reviewed gene: PYGL: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008478; Phenotypes: glycogen storage disease VI MONDO:0009294; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 CAMLG Sangavi Sivagnanasundram reviewed gene: CAMLG: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008383; Phenotypes: congenital disorder of glycosylation, type IIz MONDO:0859357; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 CYP27A1 Sangavi Sivagnanasundram reviewed gene: CYP27A1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008400; Phenotypes: cerebrotendinous xanthomatosis MONDO:0008948; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 DEGS1 Sangavi Sivagnanasundram reviewed gene: DEGS1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008468; Phenotypes: leukodystrophy, hypomyelinating, 18 MONDO:0032730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 ANAPC1 Sangavi Sivagnanasundram reviewed gene: ANAPC1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008429; Phenotypes: Rothmund-Thomson syndrome type 1 MONDO:0016368; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 COG3 Sangavi Sivagnanasundram reviewed gene: COG3: Rating: AMBER; Mode of pathogenicity: Other; Publications: https://search.clinicalgenome.org/CCID:008379; Phenotypes: congenital disorder of glycosylation MONDO:0015286; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2135 POU2AF1 Bryony Thompson Classified gene: POU2AF1 as Amber List (moderate evidence)
Mendeliome v1.2135 POU2AF1 Bryony Thompson Gene: pou2af1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2134 POU2AF1 Bryony Thompson reviewed gene: POU2AF1: Rating: AMBER; Mode of pathogenicity: None; Publications: 35603192, 33571536; Phenotypes: Agammaglobulinemia MONDO:0015977; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2134 IGKC Bryony Thompson Marked gene: IGKC as ready
Mendeliome v1.2134 IGKC Bryony Thompson Gene: igkc has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2134 IGKC Bryony Thompson Classified gene: IGKC as Amber List (moderate evidence)
Mendeliome v1.2134 IGKC Bryony Thompson Gene: igkc has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2133 IGKC Bryony Thompson gene: IGKC was added
gene: IGKC was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: IGKC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IGKC were set to https://search.clinicalgenome.org/CCID:005121
Phenotypes for gene: IGKC were set to recurrent infections associated with rare immunoglobulin isotypes deficiency MONDO:0013576
Review for gene: IGKC was set to AMBER
Added comment: Antibody Deficiencies GCEP classify gene-disease association as Limited (18/05/2021) - at least 6 probands https://search.clinicalgenome.org/CCID:005121
Sources: Expert list
Mendeliome v1.2132 FLT3LG Bryony Thompson Classified gene: FLT3LG as Amber List (moderate evidence)
Mendeliome v1.2132 FLT3LG Bryony Thompson Gene: flt3lg has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2131 FLT3LG Bryony Thompson reviewed gene: FLT3LG: Rating: AMBER; Mode of pathogenicity: None; Publications: 10828034, 38701783; Phenotypes: ?Immunodeficiency 125 MIM#620926; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2131 TNFSF9 Zornitza Stark Marked gene: TNFSF9 as ready
Mendeliome v1.2131 TNFSF9 Zornitza Stark Gene: tnfsf9 has been classified as Red List (Low Evidence).
Mendeliome v1.2131 TNFSF9 Zornitza Stark gene: TNFSF9 was added
gene: TNFSF9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TNFSF9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNFSF9 were set to 35657354
Phenotypes for gene: TNFSF9 were set to Hereditary susceptibility to infections, MONDO:0015979, TNFSF9-related
Review for gene: TNFSF9 was set to RED
Added comment: Fournier et al. described one patient with DiGeorge syndrome with a unique susceptibility to EBV with broad EBV infection and smooth muscle tumors. He was found to have a homozygous missense variant (p.V140G) in TNFSF9 coding for CD137L/4-1BBL, the ligand of the T cell co-stimulatory molecule CD137/4-1BB, whose deficiency predisposes to EBV infection.

They show that CD137LV140G mutant was weakly expressed on patient cells or when ectopically expressed in HEK and P815 cells. Importantly, patient EBV-infected B cells failed to trigger the expansion of EBV-specific T cells, resulting in decreased T cell effector responses. T cell expansion was recovered when CD137L expression was restored on B cells.
Sources: Literature
Mendeliome v1.2130 APOA4 Zornitza Stark Marked gene: APOA4 as ready
Mendeliome v1.2130 APOA4 Zornitza Stark Gene: apoa4 has been classified as Green List (High Evidence).
Mendeliome v1.2130 APOA4 Zornitza Stark Classified gene: APOA4 as Green List (high evidence)
Mendeliome v1.2130 APOA4 Zornitza Stark Gene: apoa4 has been classified as Green List (High Evidence).
Mendeliome v1.2129 APOA4 Zornitza Stark gene: APOA4 was added
gene: APOA4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: APOA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: APOA4 were set to 38096951
Phenotypes for gene: APOA4 were set to Hereditary amyloidosis, MONDO:0018634, APOA4-related
Review for gene: APOA4 was set to GREEN
Added comment: 5 families with autosomal dominant medullary amyloidosis. WGS/WES identified 2 different variants in the APOA4 gene (p.D33N in 3 families and p.L66V in 2 families). The variants were absent in gnomAD, located at the structurally flexible N-terminal domain of APOA4, and segregated with disease. There were 48 genotype +ve individuals with 44/48 having an eGFR <60. All clinically affected individuals presented with a bland urinary sediment, CKD, and no clinical evidence of systemic amyloidosis. Mean age of dialysis/transplantation was 58+/-11yrs. Routine kidney biopsies limited to the kidney cortex showed tubulointerstitial fibrosis and secondary glomerulosclerosis and no amyloid deposition. Four affected individuals were shown to have isolated medullary deposition of amyloid, with mass spectrometry showing the mutated Apoa4 as the primary constituent in 3 available cases. Plasma total ApoA4 levels were increased for patients (n=15) with ApoA4 mutations versus controls (n=49). They hypothesize that the amino acid substitutions alter the tertiary or quaternary structure of the mutated ApoA4, leading to increased plasma and primary urine concentrations and isolated medullary amyloid deposition.
Sources: Literature
Mendeliome v1.2128 TAPBP Bryony Thompson Publications for gene: TAPBP were set to 12149238
Mendeliome v1.2127 TAPBP Bryony Thompson Classified gene: TAPBP as Amber List (moderate evidence)
Mendeliome v1.2127 TAPBP Bryony Thompson Gene: tapbp has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2126 TAPBP Bryony Thompson reviewed gene: TAPBP: Rating: AMBER; Mode of pathogenicity: None; Publications: 38866210, 12149238; Phenotypes: MHC class I deficiency MONDO:0011476; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2126 RHOH Bryony Thompson Publications for gene: RHOH were set to 22850876; 27574848
Mendeliome v1.2125 RHOH Bryony Thompson Classified gene: RHOH as Amber List (moderate evidence)
Mendeliome v1.2125 RHOH Bryony Thompson Gene: rhoh has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2124 RHOH Bryony Thompson reviewed gene: RHOH: Rating: AMBER; Mode of pathogenicity: None; Publications: 38775840, 22850876; Phenotypes: epidermodysplasia verruciformis, susceptibility to, 4 MONDO:0032666; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2124 PRIM1 Bryony Thompson Classified gene: PRIM1 as Green List (high evidence)
Mendeliome v1.2124 PRIM1 Bryony Thompson Gene: prim1 has been classified as Green List (High Evidence).
Mendeliome v1.2123 PRIM1 Bryony Thompson reviewed gene: PRIM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33060134, 38773012; Phenotypes: primordial dwarfism-immunodeficiency-lipodystrophy syndrome MONDO:0859276; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2123 MAN2B2 Bryony Thompson Publications for gene: MAN2B2 were set to 31775018; 35637269
Mendeliome v1.2122 MAN2B2 Bryony Thompson reviewed gene: MAN2B2: Rating: AMBER; Mode of pathogenicity: None; Publications: 38622837, 35637269, 31775018; Phenotypes: Congenital disorder of glycosylation, MONDO:0015286, MAN2B2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2122 NUDCD3 Bryony Thompson Marked gene: NUDCD3 as ready
Mendeliome v1.2122 NUDCD3 Bryony Thompson Gene: nudcd3 has been classified as Green List (High Evidence).
Mendeliome v1.2122 NUDCD3 Bryony Thompson Classified gene: NUDCD3 as Green List (high evidence)
Mendeliome v1.2122 NUDCD3 Bryony Thompson Gene: nudcd3 has been classified as Green List (High Evidence).
Mendeliome v1.2120 NUDCD3 Bryony Thompson gene: NUDCD3 was added
gene: NUDCD3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: NUDCD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUDCD3 were set to 38787962
Phenotypes for gene: NUDCD3 were set to severe combined immunodeficiency MONDO:0015974
Mendeliome v1.2119 ATG9A Bryony Thompson Marked gene: ATG9A as ready
Mendeliome v1.2119 ATG9A Bryony Thompson Gene: atg9a has been classified as Red List (Low Evidence).
Mendeliome v1.2119 ATG9A Bryony Thompson gene: ATG9A was added
gene: ATG9A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATG9A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG9A were set to 35838483
Phenotypes for gene: ATG9A were set to Autophagy-associated immune dysregulation and hyperplasia
Review for gene: ATG9A was set to RED
Added comment: A single case with compound heterozygous variants was reported. After infection with Epstein-Barr virus (EBV), the patient developed hyperplastic proliferation of T and B cells in the lung and brain and exhibited defects in lymphocyte memory cell populations. In vitro functional assays.
Sources: Literature
Mendeliome v1.2118 CCR2 Bryony Thompson Phenotypes for gene: CCR2 were changed from {HIV infection, susceptibility/resistance to} to {HIV infection, susceptibility/resistance to}; Polycystic lung disease MIM#219600
Mendeliome v1.2117 CCR2 Bryony Thompson Publications for gene: CCR2 were set to 34516427; 17504215; 15167933; 17604544
Mendeliome v1.2116 CCR2 Bryony Thompson Mode of inheritance for gene: CCR2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2115 CCR2 Bryony Thompson Classified gene: CCR2 as Green List (high evidence)
Mendeliome v1.2115 CCR2 Bryony Thompson Gene: ccr2 has been classified as Green List (High Evidence).
Mendeliome v1.2114 CCR2 Bryony Thompson reviewed gene: CCR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38157855; Phenotypes: Polycystic lung disease MIM#219600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2114 ARHGEF1 Bryony Thompson Classified gene: ARHGEF1 as Amber List (moderate evidence)
Mendeliome v1.2114 ARHGEF1 Bryony Thompson Gene: arhgef1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2113 ME2 Bryony Thompson Marked gene: ME2 as ready
Mendeliome v1.2113 ME2 Bryony Thompson Gene: me2 has been classified as Red List (Low Evidence).
Mendeliome v1.2113 ME2 Bryony Thompson gene: ME2 was added
gene: ME2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ME2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ME2 were set to 39401966
Phenotypes for gene: ME2 were set to inborn disorder of energy metabolism MONDO:0019243
Review for gene: ME2 was set to RED
Added comment: A single individual with a homozygous frameshift variant from a consanguineous family. The phenotype included developmental delay, microcephaly, mild brain atrophy, peripheral
hypotonia, subtle dysmorphic features, ectopic kidney, and mild lactate elevation. Deletion of yeast ortholog of the gene resulted in growth arrest (which could be rescued).
Sources: Literature
Mendeliome v1.2112 TSHZ3 Bryony Thompson Marked gene: TSHZ3 as ready
Mendeliome v1.2112 TSHZ3 Bryony Thompson Gene: tshz3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2112 TSHZ3 Bryony Thompson Classified gene: TSHZ3 as Amber List (moderate evidence)
Mendeliome v1.2112 TSHZ3 Bryony Thompson Gene: tshz3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2111 TSHZ3 Bryony Thompson gene: TSHZ3 was added
gene: TSHZ3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TSHZ3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TSHZ3 were set to 27668656; 34919690; 36553458; 39420202
Phenotypes for gene: TSHZ3 were set to congenital anomaly of kidney and urinary tract MONDO:0019719
Review for gene: TSHZ3 was set to AMBER
Added comment: More evidence for the gene-disease association is required
PMID: 27668656 - TSHZ3 is included in the region deleted in chromosome 19q13.11 Deletion Syndrome, which includes intellectual disability and behavioural issues, congenital anomalies of the kidney and urinary tract (CAKUT)
PMID: 34919690 - haploinsufficient mouse model leads to kidney defects
PMID: 36553458 - heterozygous frameshift variant c.119_120dup p.Pro41SerfsTer79 in a case with intellectual disability, behavioural issues, pyelocaliceal dilatation, and mild urethral stenosis.
PMID: 39420202 - 12 CAKUT patients from 9/301 (3%) families carried 5 different rare heterozygous TSHZ3 missense variants. However, 1 of the variants (p.Ser58Gly) present in 5 of the families is more common in gnomAD v4.1 than you would expect for a dominant disease including 5 homozygotes (1,408/1,612,114 alleles, 5 hom, AF=0.0008734). The authors state this is not unexpected in a condition, such as CAKUT. However, the different missense variants are inherited from unaffected parents in at least 2/9 families (there was no phenotype information available for an additional 3 parents).
Sources: Literature
Mendeliome v1.2110 WDR83OS Bryony Thompson Phenotypes for gene: WDR83OS were changed from Cholestasis to complex neurodevelopmental disorder MONDO:0100038; neurodevelopmental disorder with hypercholanemia
Mendeliome v1.2109 WDR83OS Bryony Thompson Publications for gene: WDR83OS were set to 30250217
Mendeliome v1.2108 WDR83OS Bryony Thompson edited their review of gene: WDR83OS: Changed phenotypes: complex neurodevelopmental disorder MONDO:0100038, neurodevelopmental disorder with hypercholanemia
Mendeliome v1.2108 WDR83OS Bryony Thompson changed review comment from: Now 14 cases from 9 unrelated families with homozygous LoF variants. Consistent clinical features include NDD (14/14), facial dysmorphism (13/14), intractable itching (9/14), and elevated bile acids (5/6). Also, supporting null zebrafish model that recapitulates the human phenotype.; to: Now 14 cases from 9 unrelated families with homozygous LoF variants, including the family reported in 2019. Consistent clinical features include NDD (14/14), facial dysmorphism (13/14), intractable itching (9/14), and elevated bile acids (5/6). Also, supporting null zebrafish model that recapitulates the human phenotype.
Mendeliome v1.2108 WDR83OS Bryony Thompson Classified gene: WDR83OS as Green List (high evidence)
Mendeliome v1.2108 WDR83OS Bryony Thompson Gene: wdr83os has been classified as Green List (High Evidence).
Mendeliome v1.2107 WDR83OS Bryony Thompson reviewed gene: WDR83OS: Rating: GREEN; Mode of pathogenicity: None; Publications: 39471804, 30250217; Phenotypes: complex neurodevelopmental disorder MONDO:0100038; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2107 GON4L Bryony Thompson Marked gene: GON4L as ready
Mendeliome v1.2107 GON4L Bryony Thompson Gene: gon4l has been classified as Green List (High Evidence).
Mendeliome v1.2107 GON4L Bryony Thompson Classified gene: GON4L as Green List (high evidence)
Mendeliome v1.2107 GON4L Bryony Thompson Gene: gon4l has been classified as Green List (High Evidence).
Mendeliome v1.2106 GON4L Bryony Thompson gene: GON4L was added
gene: GON4L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GON4L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GON4L were set to 39500882; 21937992; 31785789; 34011629; 33077954
Phenotypes for gene: GON4L were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: GON4L was set to GREEN
Added comment: 2 LoF variants in 4 cases from 3 unrelated consanguineous families, and supporting null zebrafish model
PMID: 39500882 - 2 homozygous truncating GON4L variants [NM_001282860.2: c.62_63del, p.(Gln21Argfs*12) and c.5517+1G>A] in 3 patients from 2 consanguineous families with prenatal-onset growth impairment, developmental delay, mild intellectual disability, speech impairment, progressive and disproportionate microcephaly, facial asymmetry, congenital heart anomaly, and brain structure abnormalities.
Null zebrafish model had distinct morphological and size abnormalities in the craniofacial cartilage of zebrafish larvae
Heterozygous carriers in biallelic families were unaffected
PMID: 21937992 - a case from Iran from a consanguineous family homozygous for c.5517+1G>A with syndromic ID. No other clinical details provided

Limited evidence for AD gene-disease association - heterozygous de novo variants identified in autism studies and a congenital hydrocephalus study. But, heterozygous carriers in families with biallelic LoF variants are healthy
PMID: 31785789 - 4 (3 NS & 1 Silent) de novo GON4L variants in cases with autism (n=3) & neurodevelopmental disorder
PMID: 34011629 - 2 cases with autism spectrum disorder and de novo missense
PMID: 33077954 - a de novo splice site variant identified in a single case with congenital hydrocephalus
Sources: Literature
Mendeliome v1.2105 SGSM3 Zornitza Stark Publications for gene: SGSM3 were set to PMID: 37833060
Mendeliome v1.2104 SGSM3 Zornitza Stark Classified gene: SGSM3 as Green List (high evidence)
Mendeliome v1.2104 SGSM3 Zornitza Stark Gene: sgsm3 has been classified as Green List (High Evidence).
Mendeliome v1.2103 LSM7 Zornitza Stark Phenotypes for gene: LSM7 were changed from Leukodystrophy; foetal death to leukodystrophy MONDO:0019046, LRM7-related
Mendeliome v1.2102 DALRD3 Zornitza Stark Publications for gene: DALRD3 were set to 32427860
Mendeliome v1.2101 UBTF Zornitza Stark Phenotypes for gene: UBTF were changed from Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672; MONDO:0044701 to Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672; MONDO:0044701; Neurodevelopmental disorder, MONDO:0700092, UBTF-related
Mendeliome v1.2100 UBTF Zornitza Stark Publications for gene: UBTF were set to 28777933; 29300972
Mendeliome v1.2099 UBTF Zornitza Stark edited their review of gene: UBTF: Added comment: PMID 39366741: 3 Chinese patients with global developmental delay, intellectual disability, social challenges and dysmorphism (wide forehead, sparse eyebrows, hypertelorism, narrow palpebral fissures, single-fold eyelids, flat nasal bridge, anteverted nares, a long philtrum and a thin upper lip), but no neuroregression (but aged 1.8yrs-4.8yrs). WES with SNV/CNV analysis showed:
-nonsense variant c.1327C>T p. (Arg443Ter) - parental segregation not possible
-de novo ~46 kb deletion at 17q21.31 containing 7 genes but UBTF as only OMIM Morbid gene
-de novo ~106kb deletion at 17q21.31 containing 10 genes but UBTF as only relevant OMIM Morbid gene (other one was SLC4A1)

Propose haploinsufficiency presents with different phenotype to CONDBA which is due to GOF variant.

AMBER for this mechanism and phenotype.; Changed publications: 28777933, 29300972, 39366741; Changed phenotypes: Neurodegeneration, childhood-onset, with brain atrophy, MIM# 617672, MONDO:0044701, Neurodevelopmental disorder, MONDO:0700092, UBTF-related
Mendeliome v1.2099 MARK2 Zornitza Stark Marked gene: MARK2 as ready
Mendeliome v1.2099 MARK2 Zornitza Stark Gene: mark2 has been classified as Green List (High Evidence).
Mendeliome v1.2099 IRAK2 Zornitza Stark Marked gene: IRAK2 as ready
Mendeliome v1.2099 IRAK2 Zornitza Stark Gene: irak2 has been classified as Red List (Low Evidence).
Mendeliome v1.2099 IRAK2 Zornitza Stark Phenotypes for gene: IRAK2 were changed from Immune dysregulation, no OMIM # to Immune dysregulation, MONDO:0957790, IRAK2-related
Mendeliome v1.2098 IRAK2 Zornitza Stark reviewed gene: IRAK2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Immune dysregulation, MONDO:0957790, IRAK2-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2098 DTNA Zornitza Stark Publications for gene: DTNA were set to 29118297; 11238270; 16427346
Mendeliome v1.2097 DTNA Zornitza Stark Phenotypes for gene: DTNA were changed from Left ventricular noncompaction 1, with or without congenital heart defects, MIM# 604169 to Muscular dystrophy, MONDO:0020121, DTNA-related; Left ventricular noncompaction 1, with or without congenital heart defects, MIM# 604169
Mendeliome v1.2096 IKZF2 Zornitza Stark Phenotypes for gene: IKZF2 were changed from Immunodeficiency, MONDO:0021094, IKZF2-related; Immune dysregulation to Immunodeficiency, MONDO:0021094, IKZF2-related; Immune dysregulation; nonsyndromic genetic hearing loss MONDO:0019497, IKZF2-related
Mendeliome v1.2095 IKZF2 Zornitza Stark Publications for gene: IKZF2 were set to 34920454; 34826259
Mendeliome v1.2094 CRACR2A Sangavi Sivagnanasundram reviewed gene: CRACR2A: Rating: AMBER; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008378; Phenotypes: combined immunodeficiency MONDO:0015131; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2094 DNAH9 Sangavi Sivagnanasundram reviewed gene: DNAH9: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008406; Phenotypes: ciliary dyskinesia, primary, 40 MONDO:0032664; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2094 FUK Sangavi Sivagnanasundram reviewed gene: FUK: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008377; Phenotypes: congenital disorder of glycosylation with defective fucosylation 2 MONDO:0020777; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2094 CTPS1 Sangavi Sivagnanasundram reviewed gene: CTPS1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008376; Phenotypes: severe combined immunodeficiency due to CTPS1 deficiency MONDO:0014391; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2094 SOX6 Sangavi Sivagnanasundram reviewed gene: SOX6: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008480; Phenotypes: complex neurodevelopmental disorder MONDO:0100038; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2094 BHLHE22 Zornitza Stark Marked gene: BHLHE22 as ready
Mendeliome v1.2094 BHLHE22 Zornitza Stark Gene: bhlhe22 has been classified as Green List (High Evidence).
Mendeliome v1.2094 BHLHE22 Zornitza Stark Classified gene: BHLHE22 as Green List (high evidence)
Mendeliome v1.2094 BHLHE22 Zornitza Stark Gene: bhlhe22 has been classified as Green List (High Evidence).
Mendeliome v1.2093 BHLHE22 Zornitza Stark gene: BHLHE22 was added
gene: BHLHE22 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BHLHE22 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: BHLHE22 were set to 39502664
Phenotypes for gene: BHLHE22 were set to Neurodevelopmental disorder, MONDO:0700092, BHLHE22-related
Review for gene: BHLHE22 was set to GREEN
Added comment: Four individuals with de novo missense variants within the highly conserved helix-loop-helix domain and seven individuals from five unrelated families with a recurrent homozygous frameshift variant, p.(Gly74Alafs*18).

Individuals presented with absent or limited speech, severely impaired motor abilities, intellectual disability (ID), involuntary movements, autistic traits with stereotypies, abnormal muscle tone. The majority of individuals had partial or complete agenesis of the corpus callosum (ACC). Additional symptoms comprised epilepsy, variable dysmorphic features, and eye anomalies. One additional individual had spastic paraplegia without delayed development and ACC, expanding the phenotype to milder and later onset forms.

Mice lacking bhlhe22 show nearly complete loss of three brain comminsure, including the corpus callosum.
Sources: Literature
Mendeliome v1.2092 MRPL49 Zornitza Stark Marked gene: MRPL49 as ready
Mendeliome v1.2092 MRPL49 Zornitza Stark Gene: mrpl49 has been classified as Green List (High Evidence).
Mendeliome v1.2092 MRPL49 Zornitza Stark Classified gene: MRPL49 as Green List (high evidence)
Mendeliome v1.2092 MRPL49 Zornitza Stark Gene: mrpl49 has been classified as Green List (High Evidence).
Mendeliome v1.2091 MRPL49 Zornitza Stark gene: MRPL49 was added
gene: MRPL49 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MRPL49 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL49 were set to 39417135
Phenotypes for gene: MRPL49 were set to Mitochondrial disease, MONDO:0044970, MRPL49-related
Review for gene: MRPL49 was set to GREEN
Added comment: Five unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly and retinal dystrophy and bi-allelic variants in this gene.
Sources: Literature
Mendeliome v1.2090 SATB1 Sangavi Sivagnanasundram reviewed gene: SATB1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008481; Phenotypes: complex neurodevelopmental disorder MONDO:0100038; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2090 NT5C2 Sangavi Sivagnanasundram reviewed gene: NT5C2: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008372; Phenotypes: complex hereditary spastic paraplegia MONDO:0015150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2090 NPTX1 Sangavi Sivagnanasundram reviewed gene: NPTX1: Rating: GREEN; Mode of pathogenicity: Other; Publications: https://search.clinicalgenome.org/CCID:008403; Phenotypes: autosomal dominant cerebellar ataxia MONDO:0020380; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2090 SLC24A1 Sangavi Sivagnanasundram reviewed gene: SLC24A1: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008419; Phenotypes: inherited retinal dystrophy MONDO:0019118; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2090 C1QTNF5 Sangavi Sivagnanasundram reviewed gene: C1QTNF5: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008422; Phenotypes: inherited retinal dystrophy MONDO:0019118; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2090 EPHB2 Sangavi Sivagnanasundram reviewed gene: EPHB2: Rating: AMBER; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008367; Phenotypes: bleeding disorder, platelet-type, 22 MONDO:0032765; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2090 F12 Sangavi Sivagnanasundram reviewed gene: F12: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: hereditary angioedema type 3 MONDO:0012526; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2090 HOXA11 Sangavi Sivagnanasundram reviewed gene: HOXA11: Rating: AMBER; Mode of pathogenicity: None; Publications: 11101832; Phenotypes: radioulnar synostosis with amegakaryocytic thrombocytopenia 1 MONDO:0024558; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2090 CCDC115 Sangavi Sivagnanasundram reviewed gene: CCDC115: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008374; Phenotypes: CCDC115-CDG MONDO:0014789; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2090 IRAK2 Chirag Patel Phenotypes for gene: IRAK2 were changed from Immune dysregulation, no OMIM # to Immune dysregulation, no OMIM #
Mendeliome v1.2090 IRAK2 Chirag Patel Phenotypes for gene: IRAK2 were changed from Immunodeficiency, no OMIM # to Immune dysregulation, no OMIM #
Mendeliome v1.2089 IRAK2 Chirag Patel changed review comment from: 2 individuals with sequential or repeated invasive infections with 2 different variants in IRAK2 gene found on WES testing. The IRAK kinases function as downstream signal transductors following the activation of pathogen recognition receptors. IRAK4 gene has been associated with susceptibility to severe infections by common pyogenic bacteria.

Individual 1 had herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and a homozygous missense variant (L78P). There are no homozygous individuals in gnomAD (MAF 0.003%). No segregation testing reported.

Individual 2 had Streptococcus pneumoniae bacteremia with candidemia, and a heterozygous missense variant (R506W) which straddles between the kinase and TRAF6-binding CTD of IRAK2. There are 15 heterozygous individuals in gnomAD for this rare variant with no homozygotes (MAF 0.012%). No segregation testing reported.

Both patients’ peripheral blood mononuclear cells showed tendencies for TNFα hypo-responsiveness to representative bacterial, fungal and viral ligands, in line with subjects with IRAK defects. Immunoprecipitation platform assay to pull down TRAF6 revealed that possession of L78P or R506W variants led to reduced TRAF6 ubiquitination. The led to TRAF6 accumulation and in turn decreased TNFα production (an inflammatory cytokine to invading pathogens).

Paper does not comment on reasons for disease in biallelic and mono-allelic form.
Sources: Literature; to: PMID: 39299377
2 individuals with sequential or repeated invasive infections with 2 different variants in IRAK2 gene found on WES testing. The IRAK kinases function as downstream signal transductors following the activation of pathogen recognition receptors. IRAK4 gene has been associated with susceptibility to severe infections by common pyogenic bacteria.

Individual 1 had herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and a homozygous missense variant (L78P). There are no homozygous individuals in gnomAD (MAF 0.003%). No segregation testing reported. Individual 2 had Streptococcus pneumoniae bacteremia with candidemia, and a heterozygous missense variant (R506W) which straddles between the kinase and TRAF6-binding CTD of IRAK2. There are 15 heterozygous individuals in gnomAD for this rare variant with no homozygotes (MAF 0.012%). No segregation testing reported.

Both patients’ peripheral blood mononuclear cells showed tendencies for TNFα hypo-responsiveness to representative bacterial, fungal and viral ligands, in line with subjects with IRAK defects. Immunoprecipitation platform assay to pull down TRAF6 revealed that possession of L78P or R506W variants led to reduced TRAF6 ubiquitination. The led to TRAF6 accumulation and in turn decreased TNFα production (an inflammatory cytokine to invading pathogens). Paper does not comment on reasons for disease in biallelic and mono-allelic form.


Preprint paper:
2 individuals with immune dysregulation (1 x systemic lupus erythematosus and 1 x autoinflammatory disease) with same homozgyous exon 2 deletion in IRAK2 gene found on WES testing and confirmed with Sanger sequencing. Unaffected family members in trio were heterozygous for variant. Exon 2 encodes a proportion of the death domain, a critical protein domain for Myddosome assembly.

The patients exhibited aberrantly upregulated type I interferon (IFN) response following LPS stimulation, which was further confirmed in bone marrow-derived macrophages (BMDMs) in mice. RNA sequencing analysis indicated that PBMCs from the two patients consistently exhibited defects in activating NFkb signaling in response to LPS or R848 stimulation, as well as impaired activation of the MAPK signaling pathway. RNA sequencing demonstrated that BMDMs from Irak2 ∆ex2/∆ex2 mice exhibited defects in NFkb and MAPK signaling pathways, similar to patients’ PBMCs.
Mendeliome v1.2089 WISP3 Sangavi Sivagnanasundram reviewed gene: WISP3: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008442; Phenotypes: progressive pseudorheumatoid arthropathy of childhood MONDO:0008827; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2089 WDR60 Sangavi Sivagnanasundram reviewed gene: WDR60: Rating: GREEN; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:008443; Phenotypes: short-rib thoracic dysplasia 8 with or without polydactyly MONDO:0014214; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2089 IRAK2 Chirag Patel gene: IRAK2 was added
gene: IRAK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IRAK2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: IRAK2 were set to PMID: 39299377
Phenotypes for gene: IRAK2 were set to Immunodeficiency, no OMIM #
Review for gene: IRAK2 was set to RED
Added comment: 2 individuals with sequential or repeated invasive infections with 2 different variants in IRAK2 gene found on WES testing. The IRAK kinases function as downstream signal transductors following the activation of pathogen recognition receptors. IRAK4 gene has been associated with susceptibility to severe infections by common pyogenic bacteria.

Individual 1 had herpes simplex virus-triggered hemophagocytic lymphohistiocytosis with tuberculosis, and a homozygous missense variant (L78P). There are no homozygous individuals in gnomAD (MAF 0.003%). No segregation testing reported.

Individual 2 had Streptococcus pneumoniae bacteremia with candidemia, and a heterozygous missense variant (R506W) which straddles between the kinase and TRAF6-binding CTD of IRAK2. There are 15 heterozygous individuals in gnomAD for this rare variant with no homozygotes (MAF 0.012%). No segregation testing reported.

Both patients’ peripheral blood mononuclear cells showed tendencies for TNFα hypo-responsiveness to representative bacterial, fungal and viral ligands, in line with subjects with IRAK defects. Immunoprecipitation platform assay to pull down TRAF6 revealed that possession of L78P or R506W variants led to reduced TRAF6 ubiquitination. The led to TRAF6 accumulation and in turn decreased TNFα production (an inflammatory cytokine to invading pathogens).

Paper does not comment on reasons for disease in biallelic and mono-allelic form.
Sources: Literature
Mendeliome v1.2088 MARK2 Chirag Patel Classified gene: MARK2 as Green List (high evidence)
Mendeliome v1.2088 MARK2 Chirag Patel Gene: mark2 has been classified as Green List (High Evidence).
Mendeliome v1.2087 MARK2 Chirag Patel gene: MARK2 was added
gene: MARK2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MARK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MARK2 were set to PMID: 39419027, 39436150
Phenotypes for gene: MARK2 were set to Neurodevelopmental disorder MONDO:0700092
Mode of pathogenicity for gene: MARK2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: MARK2 was set to GREEN
Added comment: 31 individuals with autism spectrum disorder (30/31), intellectual disability/developmental delay (100%), motor delay (62%), speech-language problems (100%), seizure/epilepsy (46%), behaviour disorders (ADHD, aggression, anxiety)(74%), and distinctive facial features (narrow face, abnormal or broad forehead, downslanting palpebral fissures, and large or dysplastic ears).

WES/WGS identified 25 LOF and 6 missense variants in MARK2 gene (Microtubule affinity-regulating kinase 2) which contributes to establishing neuronal polarity and developing dendritic spines. LOF variants were de novo (16/25), inherited (4/25), or unk (5/25). All 6 missense variants were de novo and clustered in the kinase or KA1 domains.

The mRNA and protein expression of MARK2 in PBMCs were significantly lower in affected individuals with LOF variants than in the control group. In vitro expression assay of missense variants supported the effect of MARK2 loss. Proband-derived and CRISPR-engineered isogenic induced pluripotent stem cells (iPSCs) showed MARK2 loss leads to early neuronal developmental and functional deficits, including anomalous polarity and disorganization in neural rosettes, as well as imbalanced proliferation and differentiation in neural progenitor cells (NPCs). Mark2+/- mice showed abnormal cortical formation and partition and ASD-like behaviour. Through the use of RNA sequencing (RNA-seq) and lithium treatment, they linked MARK2 loss to downregulation of the WNT/β-catenin signaling pathway and identified lithium as a potential drug for treating MARK2-associated ASD.
Sources: Literature
Mendeliome v1.2086 DTNA Chirag Patel Classified gene: DTNA as Green List (high evidence)
Mendeliome v1.2086 DTNA Chirag Patel Gene: dtna has been classified as Green List (High Evidence).
Mendeliome v1.2085 DTNA Chirag Patel reviewed gene: DTNA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36799992; Phenotypes: Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis MONDO:0859322; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2085 KAT2B Ain Roesley Marked gene: KAT2B as ready
Mendeliome v1.2085 KAT2B Ain Roesley Gene: kat2b has been classified as Red List (Low Evidence).
Mendeliome v1.2085 KAT2B Ain Roesley Phenotypes for gene: KAT2B were changed from steroid-resistant nephrotic syndrome MONDO:0044765, KAT2B-related to steroid-resistant nephrotic syndrome MONDO:0044765, KAT2B-related; cataract MONDO:0005129, KAT2B-related
Mendeliome v1.2084 ROCK2 Sangavi Sivagnanasundram gene: ROCK2 was added
gene: ROCK2 was added to Mendeliome. Sources: ClinGen
Mode of inheritance for gene: ROCK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ROCK2 were set to 28554332, 30622330, 31941532
Phenotypes for gene: ROCK2 were set to congenital heart disease MONDO:0005453
Review for gene: ROCK2 was set to AMBER
Added comment: Reported in 4 unrelated individuals however classified as LIMITED by ClinGen Congenital Heart Disease GCEP on 03/09/2024 - https://search.clinicalgenome.org/CCID:008432
Sources: ClinGen
Mendeliome v1.2084 KAT2B Ain Roesley gene: KAT2B was added
gene: KAT2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KAT2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KAT2B were set to 39366742
Phenotypes for gene: KAT2B were set to steroid-resistant nephrotic syndrome MONDO:0044765, KAT2B-related
Review for gene: KAT2B was set to RED
gene: KAT2B was marked as current diagnostic
Added comment: 1 family with 2 affected siblings homozygous for an NMD-predicted variant

both have steroid-resistant nephrotic syndrome and bilateral cataract
only 1 has FSGS
Sources: Literature
Mendeliome v1.2083 IKZF2 Ain Roesley edited their review of gene: IKZF2: Changed rating: GREEN
Mendeliome v1.2083 IKZF2 Ain Roesley reviewed gene: IKZF2: Rating: ; Mode of pathogenicity: None; Publications: PMID: 39406892; Phenotypes: nonsyndromic genetic hearing loss MONDO:0019497, IKZF2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.2083 ANKRD24 Ain Roesley Marked gene: ANKRD24 as ready
Mendeliome v1.2083 ANKRD24 Ain Roesley Gene: ankrd24 has been classified as Red List (Low Evidence).
Mendeliome v1.2083 ANKRD24 Ain Roesley gene: ANKRD24 was added
gene: ANKRD24 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ANKRD24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ANKRD24 were set to PMID: 39434538
Phenotypes for gene: ANKRD24 were set to sensorineural hearing loss disorder MONDO:0020678, ANKRD24-related
Review for gene: ANKRD24 was set to RED
gene: ANKRD24 was marked as current diagnostic
Added comment: 1 consanguineous family with postlingual, moderate-to-severe autosomal recessive SNHL

2 affecteds homozygous for c.1934_1937del; (p.Thr645Lysfs*52), which is NMD-predicted
Sources: Literature
Mendeliome v1.2082 DALRD3 Sangavi Sivagnanasundram reviewed gene: DALRD3: Rating: AMBER; Mode of pathogenicity: None; Publications: 39482881; Phenotypes: developmental and epileptic encephalopathy, 86 MONDO:0030054; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2082 ZNF862 Ain Roesley Marked gene: ZNF862 as ready
Mendeliome v1.2082 ZNF862 Ain Roesley Gene: znf862 has been classified as Red List (Low Evidence).
Mendeliome v1.2082 ZNF862 Ain Roesley gene: ZNF862 was added
gene: ZNF862 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF862 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNF862 were set to PMID: 35142290
Phenotypes for gene: ZNF862 were set to hereditary gingival fibromatosis MONDO:0016070 , ZNF862 -related
Review for gene: ZNF862 was set to RED
gene: ZNF862 was marked as current diagnostic
Added comment: 13 individuals in a large multi-generational family with hereditary gingival fibromatosis

missense variant with 5 hets in gnomad v4, very low conservation and benign REVEL score
Sources: Literature
Mendeliome v1.2081 LSM7 Sangavi Sivagnanasundram reviewed gene: LSM7: Rating: AMBER; Mode of pathogenicity: None; Publications: 39420558; Phenotypes: leukodystrophy MONDO:0019046; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2081 LAMA3 Ain Roesley Phenotypes for gene: LAMA3 were changed from Epidermolysis bullosa, generalized atrophic benign, MIM# 226650; Epidermolysis bullosa, junctional, Herlitz type, MIM# 226700 to Epidermolysis bullosa, junctional 2A, intermediate MIM#619783; Epidermolysis bullosa, junctional 2B, severe MIM#619784; Epidermolysis bullosa, junctional 2C, laryngoonychocutaneous MIM#245660
Mendeliome v1.2080 SGSM3 Sangavi Sivagnanasundram reviewed gene: SGSM3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39390489; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), SGSM3-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2080 GMNN Zornitza Stark changed review comment from: Three unrelated individuals reported, all variants in exon 2 (first coding exon).; to: Three unrelated individuals reported, all variants in exon 2 (first coding exon), leading to the expression of a stable truncated protein.
Mendeliome v1.2080 LINC01578 Zornitza Stark Marked gene: LINC01578 as ready
Mendeliome v1.2080 LINC01578 Zornitza Stark Gene: linc01578 has been classified as Green List (High Evidence).
Mendeliome v1.2080 LINC01578 Zornitza Stark Publications for gene: LINC01578 were set to
Mendeliome v1.2079 LINC01578 Zornitza Stark edited their review of gene: LINC01578: Changed publications: 39442041
Mendeliome v1.2079 LINC01578 Zornitza Stark Classified gene: LINC01578 as Green List (high evidence)
Mendeliome v1.2079 LINC01578 Zornitza Stark Gene: linc01578 has been classified as Green List (High Evidence).
Mendeliome v1.2078 LINC01578 Zornitza Stark gene: LINC01578 was added
gene: LINC01578 was added to Mendeliome. Sources: Literature
SV/CNV, new gene name tags were added to gene: LINC01578.
Mode of inheritance for gene: LINC01578 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: LINC01578 were set to Neurodevelopmental disorder, MONDO:0700092, CHASERR-related
Review for gene: LINC01578 was set to GREEN
Added comment: CHASERR encodes a human long noncoding RNA (lncRNA) adjacent to CHD2, a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. Three unrelated children reported with a syndromic, early-onset neurodevelopmental disorder, each of whom had a de novo deletion in the CHASERR locus. The children had severe encephalopathy, shared facial dysmorphisms, cortical atrophy, and cerebral hypomyelination - a phenotype that is distinct from the phenotypes of patients with CHD2 haploinsufficiency. CHASERR deletion results in increased CHD2 protein abundance in patient-derived cell lines and increased expression of the CHD2 transcript in cis, indicating bidirectional dosage sensitivity in human disease.
Sources: Literature
Mendeliome v1.2077 RNU5B-1 Zornitza Stark Marked gene: RNU5B-1 as ready
Mendeliome v1.2077 RNU5B-1 Zornitza Stark Gene: rnu5b-1 has been classified as Green List (High Evidence).
Mendeliome v1.2077 RNU5B-1 Zornitza Stark Classified gene: RNU5B-1 as Green List (high evidence)
Mendeliome v1.2077 RNU5B-1 Zornitza Stark Gene: rnu5b-1 has been classified as Green List (High Evidence).
Mendeliome v1.2076 RNU5B-1 Zornitza Stark gene: RNU5B-1 was added
gene: RNU5B-1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU5B-1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU5B-1 were set to https://www.medrxiv.org/content/10.1101/2024.10.04.24314692v1.full.pdf; https://www.medrxiv.org/content/10.1101/2024.10.07.24314689v1
Phenotypes for gene: RNU5B-1 were set to Neurodevelopmental disorder, MONDO:0700092, RNU5B-1 related
Review for gene: RNU5B-1 was set to GREEN
Added comment: 20 individuals reported in two preprints with de novo variants in this gene and a neurodevelopmental phenotype.
Sources: Literature
Mendeliome v1.2075 SPATA22 Zornitza Stark Phenotypes for gene: SPATA22 were changed from Premature ovarian insufficiency and nonobstructive azoospermia; Genetic infertility MONDO:0017143 to Spermatogenic failure 96, MIM#621001; Premature ovarian failure 25, MIM#621002
Mendeliome v1.2074 SPATA22 Zornitza Stark edited their review of gene: SPATA22: Changed phenotypes: Spermatogenic failure 96, MIM#621001, Premature ovarian failure 25, MIM#621002
Mendeliome v1.2074 SRPK3 Zornitza Stark Phenotypes for gene: SRPK3 were changed from Myopathy, MONDO:0005336, digenic SRPK3- and TTN-related; Neurodevelopmental disorder, MONDO:0700092, SRPK3-related to Myopathy, MONDO:0005336, digenic SRPK3- and TTN-related; Intellectual developmental disorder, X-linked, 114, MIM#301134
Mendeliome v1.2073 SRPK3 Zornitza Stark edited their review of gene: SRPK3: Changed phenotypes: Myopathy, MONDO:0005336, digenic SRPK3- and TTN-related, Intellectual developmental disorder, X-linked, 114, MIM#301134
Mendeliome v1.2073 TOMM7 Eleanor Williams commented on gene: TOMM7
Mendeliome v1.2073 DHX9 Zornitza Stark Phenotypes for gene: DHX9 were changed from neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071; Charcot-Marie-Tooth disease, MONDO:0015626 to Intellectual developmental disorder, autosomal dominant 75, MIM# 620988; Charcot-Marie-Tooth disease, MONDO:0015626
Mendeliome v1.2072 DHX9 Zornitza Stark edited their review of gene: DHX9: Changed rating: GREEN; Changed phenotypes: Intellectual developmental disorder, autosomal dominant 75, MIM# 620988; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2072 ZRSR2 Zornitza Stark Phenotypes for gene: ZRSR2 were changed from Orofacialdigital syndrome MONDO:0015375, ZRSR2-related to Orofaciodigital syndrome XXI, MIM# 301132
Mendeliome v1.2071 ZRSR2 Zornitza Stark edited their review of gene: ZRSR2: Changed phenotypes: Orofaciodigital syndrome XXI, MIM# 301132
Mendeliome v1.2071 ZNF808 Zornitza Stark Phenotypes for gene: ZNF808 were changed from non-syndromic neonatal diabetes; MONDO:0016391 to Pancreatic agenesis 3, MIM# 620991
Mendeliome v1.2070 ZNF808 Zornitza Stark reviewed gene: ZNF808: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pancreatic agenesis 3, MIM# 620991; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2070 AJAP1 Zornitza Stark Marked gene: AJAP1 as ready
Mendeliome v1.2070 AJAP1 Zornitza Stark Gene: ajap1 has been classified as Green List (High Evidence).
Mendeliome v1.2070 AJAP1 Zornitza Stark Classified gene: AJAP1 as Green List (high evidence)
Mendeliome v1.2070 AJAP1 Zornitza Stark Gene: ajap1 has been classified as Green List (High Evidence).
Mendeliome v1.2069 AJAP1 Achchuthan Shanmugasundram gene: AJAP1 was added
gene: AJAP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AJAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AJAP1 were set to 38985877
Phenotypes for gene: AJAP1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: AJAP1 was set to GREEN
Added comment: PMID:38985877 reported five unrelated individuals with monoallelic variants or a deletion in AJAP1 gene and they presented with epilepsy, neurodevelopmental problems, or intellectual disability. There is also supporting functional evidence available.
Sources: Literature
Mendeliome v1.2069 DHRSX Zornitza Stark Marked gene: DHRSX as ready
Mendeliome v1.2069 DHRSX Zornitza Stark Gene: dhrsx has been classified as Green List (High Evidence).
Mendeliome v1.2069 DHRSX Zornitza Stark Classified gene: DHRSX as Green List (high evidence)
Mendeliome v1.2069 DHRSX Zornitza Stark Gene: dhrsx has been classified as Green List (High Evidence).
Mendeliome v1.2068 MSL2 Zornitza Stark Phenotypes for gene: MSL2 were changed from Neurodevelopmental disorder, MONDO:0700092, MSL2-related to Karayol-Borroto-Haghshenas neurodevelopmental syndrome, MIM# 620985
Mendeliome v1.2067 MSL2 Zornitza Stark reviewed gene: MSL2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Karayol-Borroto-Haghshenas neurodevelopmental syndrome, MIM# 620985; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2067 WFDC2 Zornitza Stark Phenotypes for gene: WFDC2 were changed from bronchiectasis, MONDO:0004822, WFDC2-related to Bronchiectasis and nasal polyposis, MIM# 620984
Mendeliome v1.2066 WFDC2 Zornitza Stark edited their review of gene: WFDC2: Changed phenotypes: Bronchiectasis and nasal polyposis, MIM# 620984
Mendeliome v1.2066 BORCS8 Zornitza Stark Phenotypes for gene: BORCS8 were changed from Neurodevelopmental disorder (MONDO#0700092), BORCS8-related to Neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities, MIM# 620987
Mendeliome v1.2065 BORCS8 Zornitza Stark reviewed gene: BORCS8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities, MIM# 620987; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2065 COPG1 Zornitza Stark Phenotypes for gene: COPG1 were changed from Combined immunodeficiency MONDO:0015131, COPG1-related to Immunodeficiency 128, MIM# 620983
Mendeliome v1.2064 COPG1 Zornitza Stark edited their review of gene: COPG1: Changed phenotypes: Immunodeficiency 128, MIM# 620983
Mendeliome v1.2064 MAL Zornitza Stark Phenotypes for gene: MAL were changed from Leukodystrophy MONDO:0019046, MAL-related to Leukodystrophy, hypomyelinating, 28, MIM# 620978
Mendeliome v1.2063 MAL Zornitza Stark edited their review of gene: MAL: Changed phenotypes: Leukodystrophy, hypomyelinating, 28, MIM# 620978
Mendeliome v1.2063 DHRSX Achchuthan Shanmugasundram commented on gene: DHRSX: Note that this gene is located in the pseudoautosomal region 1.
Mendeliome v1.2063 DHRSX Achchuthan Shanmugasundram gene: DHRSX was added
gene: DHRSX was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DHRSX was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHRSX were set to 38821050
Phenotypes for gene: DHRSX were set to congenital disorder of glycosylation, MONDO:0015286
Review for gene: DHRSX was set to GREEN
Added comment: PMID:38821050 reported the identification of biallelic missense variants in DHRSX gene in four patients from three unrelated families with a congenital disorder of glycosylation. They displayed distinct facial features, severe neurological involvement including hypotonia, scoliosis, contractures, profound intellectual disability, epilepsy, and sensorineural hearing loss. These patients also experienced severe failure to thrive (requiring tube feeding); variable respiratory insufficiency; and involvement of the eyes, the gastrointestinal system, and other organs.

This gene has not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Mendeliome v1.2063 UFC1 Zornitza Stark Tag deep intronic tag was added to gene: UFC1.
Mendeliome v1.2063 UFC1 Zornitza Stark reviewed gene: UFC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with spasticity and poor growth (MIM#618076); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2063 WFDC2 Zornitza Stark Marked gene: WFDC2 as ready
Mendeliome v1.2063 WFDC2 Zornitza Stark Gene: wfdc2 has been classified as Green List (High Evidence).
Mendeliome v1.2063 WFDC2 Zornitza Stark Classified gene: WFDC2 as Green List (high evidence)
Mendeliome v1.2063 WFDC2 Zornitza Stark Gene: wfdc2 has been classified as Green List (High Evidence).
Mendeliome v1.2062 WFDC2 Zornitza Stark gene: WFDC2 was added
gene: WFDC2 was added to Mendeliome. Sources: Literature
founder tags were added to gene: WFDC2.
Mode of inheritance for gene: WFDC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WFDC2 were set to 38626355
Phenotypes for gene: WFDC2 were set to bronchiectasis, MONDO:0004822, WFDC2-related
Review for gene: WFDC2 was set to GREEN
Added comment: 11 individuals from 10 families reported with bi-allelic variants in this gene and bronchiectasis and nasal polyps. p.Cys49Arg is recurrent and may be a founder variant.
Sources: Literature
Mendeliome v1.2061 PTCH1 Zornitza Stark Phenotypes for gene: PTCH1 were changed from Holoprosencephaly 7, MIM# 610828 to Holoprosencephaly 7, MIM# 610828; Bladder exstrophy and epispadias complex (BEEC)
Mendeliome v1.2060 BMP5 Zornitza Stark Marked gene: BMP5 as ready
Mendeliome v1.2060 BMP5 Zornitza Stark Gene: bmp5 has been classified as Red List (Low Evidence).
Mendeliome v1.2060 BMP5 Zornitza Stark Phenotypes for gene: BMP5 were changed from Skeletal dysostosis and atrioventricular septal defect, no OMIM# to Skeletal dysplasia, MONDO:0018230, BMP5-related; Skeletal dysostosis and atrioventricular septal defect, no OMIM#
Mendeliome v1.2059 BMP5 Zornitza Stark Publications for gene: BMP5 were set to
Mendeliome v1.2058 RELB Zornitza Stark Publications for gene: RELB were set to 7834753; 26385063
Mendeliome v1.2057 KLF1 Zornitza Stark Phenotypes for gene: KLF1 were changed from Dyserythropoietic anaemia, congenital, type IV, MIM# 613673; MONDO:0013355 to Dyserythropoietic anaemia, congenital, type IV, MIM# 613673; MONDO:0013355; Anaemia, congenital dyserythropoietic, type IVb, MIM#620969
Mendeliome v1.2056 KLF1 Zornitza Stark Publications for gene: KLF1 were set to 21055716; 33339573; 32815883; 32221653; 32032242; 31818881
Mendeliome v1.2055 KLF1 Zornitza Stark Mode of inheritance for gene: KLF1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2054 KLF1 Zornitza Stark edited their review of gene: KLF1: Added comment: Ten individuals reported with bi-allelic variants and congenital dyserythropoietic anaemia.; Changed publications: 21055716, 33339573, 32815883, 32221653, 32032242, 31818881, 24443441, 25724378, 28361594, 34554218; Changed phenotypes: Dyserythropoietic anaemia, congenital, type IV, MIM# 613673, MONDO:0013355, Anaemia, congenital dyserythropoietic, type IVb, MIM#620969; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2054 POLR3K Bryony Thompson Phenotypes for gene: POLR3K were changed from Hypomyelinating leukodystrophy-21, MIM#619310 to POLR3-related leukodystrophy MONDO:0700282
Mendeliome v1.2053 POLR3K Bryony Thompson Publications for gene: POLR3K were set to 30584594; 33659930
Mendeliome v1.2052 POLR3K Bryony Thompson Classified gene: POLR3K as Green List (high evidence)
Mendeliome v1.2052 POLR3K Bryony Thompson Gene: polr3k has been classified as Green List (High Evidence).
Mendeliome v1.2051 POLR3K Bryony Thompson reviewed gene: POLR3K: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.1155/2024/8807171, 30584594; Phenotypes: POLR3-related leukodystrophy MONDO:0700282; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2051 RELB Chirag Patel Classified gene: RELB as Green List (high evidence)
Mendeliome v1.2051 RELB Chirag Patel Gene: relb has been classified as Green List (High Evidence).
Mendeliome v1.2050 RELB Chirag Patel reviewed gene: RELB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39231201; Phenotypes: T-cell and B cell immunodeficiency, Immunodeficiency 53, OMIM #617585; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2049 BMP5 Chirag Patel edited their review of gene: BMP5: Changed publications: PMID: 39239663
Mendeliome v1.2048 BMP5 Chirag Patel gene: BMP5 was added
gene: BMP5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BMP5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BMP5 were set to Skeletal dysostosis and atrioventricular septal defect, no OMIM#
Phenotypes for gene: BMP5 were set to Skeletal dysostosis and atrioventricular septal defect, no OMIM#
Review for gene: BMP5 was set to RED
Added comment: 1 patient with skeletal dysostosis, atrioventricular septal defect, hypermobility, laryngo-tracheo-bronchomalacia and dysmorphic features (malar hypoplasia, short palpebral fissures, short nose, low nasal bridge, anteverted nares, long philtrum, small ears with abnormally folded antihelix). Skeletal survey showed mild thoracolumbar scoliosis, four sacral segments, absent ossification of the inferior pubic rami, and patellar aplasia. Trio WGS identified compound heterozygous loss of function variants in BMP5 (c.88_89del, p.(Gly30Argfs*11) and c.1104+2del, p.(?). Abnormal splicing was proven on the suspected splice variant using maternal fibroblasts. BMP5 expression is confined to specific parts of the skeleton and cartilage in mice and is tightly regulated by different enhancers. Previous studies of chicken embryonic heart development showed BMP5 expression in the endoderm underlying the precardiac mesoderm, the myocardium of the atrioventricular canal and outflow tract regions. Other bone morphogenetic proteins are linked to several genetic skeletal disorders.
Sources: Literature
Mendeliome v1.2047 IL7 Zornitza Stark Marked gene: IL7 as ready
Mendeliome v1.2047 IL7 Zornitza Stark Gene: il7 has been classified as Green List (High Evidence).
Mendeliome v1.2047 IL7 Zornitza Stark Classified gene: IL7 as Green List (high evidence)
Mendeliome v1.2047 IL7 Zornitza Stark Gene: il7 has been classified as Green List (High Evidence).
Mendeliome v1.2046 IL7 Zornitza Stark gene: IL7 was added
gene: IL7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IL7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL7 were set to 39352394
Phenotypes for gene: IL7 were set to Combined immunodeficiency, MONDO:0015131, IL7-related
Review for gene: IL7 was set to GREEN
Added comment: 6 indviduals from 4 kindreds with combined immune deficiency and recurrent infections. Extensive immunophenotyping revealing IL7 dependent and independent development of T cells.
Sources: Literature
Mendeliome v1.2045 LRRC7 Zornitza Stark Marked gene: LRRC7 as ready
Mendeliome v1.2045 LRRC7 Zornitza Stark Gene: lrrc7 has been classified as Green List (High Evidence).
Mendeliome v1.2045 LRRC7 Zornitza Stark Phenotypes for gene: LRRC7 were changed from neurodevelopmental disorder (MONDO:0700092) to neurodevelopmental disorder (MONDO:0700092), LRRC7-related
Mendeliome v1.2044 LRRC7 Zornitza Stark Classified gene: LRRC7 as Green List (high evidence)
Mendeliome v1.2044 LRRC7 Zornitza Stark Gene: lrrc7 has been classified as Green List (High Evidence).
Mendeliome v1.2043 LRRC7 Zornitza Stark reviewed gene: LRRC7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: neurodevelopmental disorder (MONDO:0700092), LRRC7-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2043 RPL26 Zornitza Stark Phenotypes for gene: RPL26 were changed from Diamond-Blackfan anemia 11, MIM# 614900 to Diamond-Blackfan anaemia 11, MIM# 614900
Mendeliome v1.2042 RPL26 Zornitza Stark Publications for gene: RPL26 were set to 22431104
Mendeliome v1.2041 RPL26 Zornitza Stark Classified gene: RPL26 as Green List (high evidence)
Mendeliome v1.2041 RPL26 Zornitza Stark Gene: rpl26 has been classified as Green List (High Evidence).
Mendeliome v1.2040 FLVCR1 Zornitza Stark Phenotypes for gene: FLVCR1 were changed from posterior column ataxia-retinitis pigmentosa syndrome MONDO:0012177 to posterior column ataxia-retinitis pigmentosa syndrome MONDO:0012177; neurodevelopmental disorder MONDO:0700092, FLVCR1-related
Mendeliome v1.2039 NHEJ1 Zornitza Stark Phenotypes for gene: NHEJ1 were changed from Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, MIM# 611291; Cernunnos-XLF deficiency MONDO:0012650 to Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, MIM# 611291; Cernunnos-XLF deficiency MONDO:0012650; Microphthalmia/coloboma, MIM# 13 620968
Mendeliome v1.2038 NHEJ1 Zornitza Stark Publications for gene: NHEJ1 were set to 30898087; 30666249; 28741180; 25288157; 24511403; 21721379; 21535335
Mendeliome v1.2037 NHEJ1 Zornitza Stark changed review comment from: PMID 37580330: Seven individuals from 2 consanguineous families identified with a deep intronic homozygous variant affecting the IHH enhancer within NHEJ1.; to: PMID 37580330: Seven individuals from 2 consanguineous families identified with a deep intronic homozygous variant affecting the IHH enhancer within NHEJ1 -- RED for this association.
Mendeliome v1.2037 NHEJ1 Zornitza Stark edited their review of gene: NHEJ1: Added comment: PMID 37580330: Seven individuals from 2 consanguineous families identified with a deep intronic homozygous variant affecting the IHH enhancer within NHEJ1.; Changed publications: 30898087, 30666249, 28741180, 25288157, 24511403, 21721379, 21535335, 37580330; Changed phenotypes: Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation, MIM# 611291, Cernunnos-XLF deficiency MONDO:0012650, Microphthalmia/coloboma, MIM# 13 620968
Mendeliome v1.2037 FLVCR1 Bryony Thompson edited their review of gene: FLVCR1: Added comment: A study with 30 patients from 23 unrelated families with biallelic ultra-rare missense and predicted loss-of-function variants in FLVCR1 with a novel FLVCR1-related phenotype characterised by severe developmental disorders with profound developmental delay, microcephaly, brain malformations, epilepsy, spasticity, and premature death. Optic disk atrophy, limb and digital malformations, and macrocytic anaemia can be present.; Changed publications: 21070897, 22279524, 21267618, 39306721; Changed phenotypes: posterior column ataxia-retinitis pigmentosa syndrome MONDO:0012177, neurodevelopmental disorder MONDO:0700092, FLVCR1-related
Mendeliome v1.2037 RPL26 Sangavi Sivagnanasundram reviewed gene: RPL26: Rating: GREEN; Mode of pathogenicity: None; Publications: 39268718; Phenotypes: Diamond-Blackfan anemia MONDO:0015253; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2037 LRRC7 Sangavi Sivagnanasundram gene: LRRC7 was added
gene: LRRC7 was added to Mendeliome. Sources: Other,Literature
Mode of inheritance for gene: LRRC7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LRRC7 were set to 39256359
Phenotypes for gene: LRRC7 were set to neurodevelopmental disorder (MONDO:0700092)
Review for gene: LRRC7 was set to GREEN
Added comment: Well established gene-disease association.
Neurodevelopmental disorder with a clinical spectrum - symptoms include ID, ADHD, aggression and in many cases, hyperphagia associate obesity.
Heterozygous missense and LoF variants have been reported and functional assays were conducted on missense and truncating variants that support LoF mechanism of disease.
Sources: Other, Literature
Mendeliome v1.2037 GMPPB Ain Roesley Phenotypes for gene: GMPPB were changed from Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 615350; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14 615351; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 615352 to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 (MIM# 615350); Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 14 (MIM# 615351); Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 (MIM# 615352)
Mendeliome v1.2036 GMPPA Ain Roesley Phenotypes for gene: GMPPA were changed from Alacrima, achalasia, and mental retardation syndrome, MIM# 615510 to Alacrima, achalasia, and impaired intellectual development syndrome (MIM# 615510)
Mendeliome v1.2035 USP9X Ain Roesley Phenotypes for gene: USP9X were changed from Mental retardation, X-linked 99, XLR (MIM#300919) and XLD (MIM#300968) to Intellectual developmental disorder 99 MIM#300919; syndromic, female-restricted Intellectual developmental disorder 99 MIM#300968
Mendeliome v1.2034 IL7R Ain Roesley Phenotypes for gene: IL7R were changed from Severe combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive type MIM# 608971; fever; rash; failure to thrive; recurrent respiratory and gastric infections; diarrhoea; lymphadenopathy; pneumonitis; Pancytopaenia; low T-cell numbers; decreased immunoglobulins; normal-high B/NK-cell numbers. to severe combined immunodeficiency 104 MIM#608971
Mendeliome v1.2033 SGPL1 Ain Roesley Phenotypes for gene: SGPL1 were changed from to RENI syndrome (MIM#617575)
Mendeliome v1.2032 PPP2R5D Ain Roesley Phenotypes for gene: PPP2R5D were changed from Mental retardation, autosomal dominant 35, MIM#616355 to Houge-Janssens syndrome 1, MIM#616355
Mendeliome v1.2031 ATAD2B Ain Roesley Marked gene: ATAD2B as ready
Mendeliome v1.2031 ATAD2B Ain Roesley Gene: atad2b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2031 ATAD2B Ain Roesley Classified gene: ATAD2B as Amber List (moderate evidence)
Mendeliome v1.2031 ATAD2B Ain Roesley Gene: atad2b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2030 ATAD2B Ain Roesley gene: ATAD2B was added
gene: ATAD2B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATAD2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATAD2B were set to 39313616
Phenotypes for gene: ATAD2B were set to neurodevelopmental disorder MONDO:0700092, ATAD2B-related
Review for gene: ATAD2B was set to AMBER
gene: ATAD2B was marked as current diagnostic
Added comment: 3 families including 2 siblings
1 fam is hom for a highly conserved missense

Amber because of the lack of specific phenotypes:
Abnormality of the nervous system and Abnormality of the eye
Sources: Literature
Mendeliome v1.2029 ZDHHC16 Ain Roesley Classified gene: ZDHHC16 as Amber List (moderate evidence)
Mendeliome v1.2029 ZDHHC16 Ain Roesley Gene: zdhhc16 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2028 ZDHHC16 Ain Roesley Marked gene: ZDHHC16 as ready
Mendeliome v1.2028 ZDHHC16 Ain Roesley Gene: zdhhc16 has been classified as Red List (Low Evidence).
Mendeliome v1.2028 ZDHHC16 Ain Roesley gene: ZDHHC16 was added
gene: ZDHHC16 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZDHHC16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZDHHC16 were set to 39313616
Phenotypes for gene: ZDHHC16 were set to neurodevelopmental disorder MONDO:0700092, ZDHHC16-related
Review for gene: ZDHHC16 was set to AMBER
gene: ZDHHC16 was marked as current diagnostic
Added comment: 6 families including a pair of siblings

Amber because 5 of the families had non specific phenotypes listed
Abnormality of:
the nervous system, metabolism/homeostasis, head/neck, immune system, the integument, the digestive system, the respiratory system, the endocrine system, Growth abnormality the skeletal system, the musculature, the eye

Specific HPOs were provided for one individual (homoyzygous for a canonical splice)

Abnormality of the face; Cerebellar hypoplasia; Developmental regression; Encephalopathy; Hyperreflexia; Hypertonia; Hypotonia; Inguinal hernia; Laryngomalacia; Microcephaly; Motor delay; Optic atrophy; Seizure; Spastic paraparesis; Spasticity; Talipes equinovarus; Umbilical hernia
Sources: Literature
Mendeliome v1.2027 KBTBD2 Ain Roesley Marked gene: KBTBD2 as ready
Mendeliome v1.2027 KBTBD2 Ain Roesley Gene: kbtbd2 has been classified as Green List (High Evidence).
Mendeliome v1.2027 KBTBD2 Ain Roesley Classified gene: KBTBD2 as Green List (high evidence)
Mendeliome v1.2027 KBTBD2 Ain Roesley Gene: kbtbd2 has been classified as Green List (High Evidence).
Mendeliome v1.2026 KBTBD2 Ain Roesley gene: KBTBD2 was added
gene: KBTBD2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KBTBD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KBTBD2 were set to 39313616
Phenotypes for gene: KBTBD2 were set to neurodevelopmental disorder MONDO:0700092, KBTBD2-related
Review for gene: KBTBD2 was set to GREEN
gene: KBTBD2 was marked as current diagnostic
Added comment: 3 families - 2 compound hets and 1 hom

phenotypes include:
Microcephaly, hypotonia, failure to thrive, IUGR, delayed gross motor development, dysmorphism
Sources: Literature
Mendeliome v1.2025 EPB41L3 Bryony Thompson Marked gene: EPB41L3 as ready
Mendeliome v1.2025 EPB41L3 Bryony Thompson Gene: epb41l3 has been classified as Green List (High Evidence).
Mendeliome v1.2025 EPB41L3 Bryony Thompson Classified gene: EPB41L3 as Green List (high evidence)
Mendeliome v1.2025 EPB41L3 Bryony Thompson Gene: epb41l3 has been classified as Green List (High Evidence).
Mendeliome v1.2024 EPB41L3 Bryony Thompson gene: EPB41L3 was added
gene: EPB41L3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EPB41L3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EPB41L3 were set to 39292993
Phenotypes for gene: EPB41L3 were set to neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities MONDO:0030063
Review for gene: EPB41L3 was set to GREEN
Added comment: 6 cases from 5 unrelated consanguineous families (2nd & 3rd degree) with homozygous LoF variants and a neurodevelopmental condition, including ID and seizures. Epb41l3 shRNA-mediated downregulation in mouse oligodendroglia demonstrated impaired oligodendrocyte function.
Sources: Literature
Mendeliome v1.2023 PSKH1 Zornitza Stark Marked gene: PSKH1 as ready
Mendeliome v1.2023 PSKH1 Zornitza Stark Gene: pskh1 has been classified as Green List (High Evidence).
Mendeliome v1.2023 PSKH1 Zornitza Stark Classified gene: PSKH1 as Green List (high evidence)
Mendeliome v1.2023 PSKH1 Zornitza Stark Gene: pskh1 has been classified as Green List (High Evidence).
Mendeliome v1.2022 PSKH1 Zornitza Stark gene: PSKH1 was added
gene: PSKH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSKH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSKH1 were set to 39132680
Phenotypes for gene: PSKH1 were set to Cholestasis, progressive familial intrahepatic, 13, MIM# 620962
Review for gene: PSKH1 was set to GREEN
Added comment: 4 consanguineous families (out of 279 families) with intrahepatic cholestasis:
-1 patient died at 10mths with cholestasis/liver impairment and kidney impairment
-3 cousins with cholestasis (2 with liver failure needing transplant) and kidney features (2 with kidney failure, 1 with renal echogenicity)
-2 siblings with hepatic fibrosis (1 with unilateral renal agenesis)
-2 siblings with unexplained liver cirrhosis (1 needing transplant) but normal kidney function

WES identified 3 different homozygous variants in PSKH1 (Arg121Trp, Ile126Val, Arg183Cys). Patient fibroblasts displayed abnormal cilia that are long and show abnormal transport. A homozygous Pskh1 mutant mouse faithfully recapitulated the human phenotype and displayed abnormally long cilia. The phenotype could be rationalized by the loss of catalytic activity observed for each recombinant PSKH1 variant using in vitro kinase assays. Human PSKH1 is a poorly understood gene that may play important role in intracellular trafficking, is sensitive to intracellular Ca2+ concentration, and is localized to centrosomes, suggesting a link to cystogenesis.
Sources: Literature
Mendeliome v1.2021 CIAO1 Zornitza Stark Phenotypes for gene: CIAO1 were changed from Neurodegenerative disease, MONDO:0005559, CIAO1-related to Multiple mitochondrial dysfunctions syndrome 10, MIM#620960
Mendeliome v1.2020 CIAO1 Zornitza Stark reviewed gene: CIAO1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Multiple mitochondrial dysfunctions syndrome 10, MIM#620960; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2020 TREM2 Zornitza Stark Phenotypes for gene: TREM2 were changed from Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, MIM# 618193 to Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, MIM# 618193; {Alzhieimer disease 17, susceptibility to}, MIM# 615080
Mendeliome v1.2019 TREM2 Zornitza Stark edited their review of gene: TREM2: Changed phenotypes: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, MIM# 618193, {Alzhieimer disease 17, susceptibility to}, MIM# 615080
Mendeliome v1.2019 JPH1 Zornitza Stark Phenotypes for gene: JPH1 were changed from Congenital myopathy MONDO:0019952 to Congenital myopathy 25, MIM# 620964
Mendeliome v1.2018 JPH1 Zornitza Stark reviewed gene: JPH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital myopathy 25, MIM# 620964; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2018 AHR Zornitza Stark Phenotypes for gene: AHR were changed from ?Retinitis pigmentosa 85 MIM#618345; foveal hypoplasia and infantile nystagmus to Retinitis pigmentosa 85 MIM#618345; Foveal hypoplasia 3, MIM# 620958
Mendeliome v1.2017 AHR Zornitza Stark edited their review of gene: AHR: Changed phenotypes: Foveal hypoplasia 3, MIM# 620958
Mendeliome v1.2017 PSTPIP1 Zornitza Stark Phenotypes for gene: PSTPIP1 were changed from Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416; PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome to Autoinflammatory syndrome with cytopenia, hyperzincemia, and hypercalprotectinemia, MIMM# 601979; Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416; PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome
Mendeliome v1.2016 PSTPIP1 Zornitza Stark edited their review of gene: PSTPIP1: Changed phenotypes: Autoinflammatory syndrome with cytopenia, hyperzincemia, and hypercalprotectinemia, MIMM# 601979, Pyogenic sterile arthritis, pyoderma gangrenosum, and acne, MIM# 604416, PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome
Mendeliome v1.2016 PNKP Shakira Heerah Deleted their review
Mendeliome v1.2016 RPS6KB1 Bryony Thompson Classified gene: RPS6KB1 as Amber List (moderate evidence)
Mendeliome v1.2016 RPS6KB1 Bryony Thompson Added comment: Comment on list classification: Comment on list classification: ClinGen HCVD GCEP has classified this gene as Limited for HCM on 13/09/2023 - https://search.clinicalgenome.org/CCID:006034
Mendeliome v1.2016 RPS6KB1 Bryony Thompson Gene: rps6kb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2015 DNAH6 Seb Lunke reviewed gene: DNAH6: Rating: AMBER; Mode of pathogenicity: None; Publications: 34215651; Phenotypes: situs inversus, MONDO:0010029, transposition of the great arteries, MONDO:0000153; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2015 EXOC3L2 Zornitza Stark Phenotypes for gene: EXOC3L2 were changed from Dandy-Walker malformation, MONDO:0009072; renal dysplasia; bone marrow failure to Brain malformation renal syndrome, MIM# 620943
Mendeliome v1.2014 EXOC3L2 Zornitza Stark edited their review of gene: EXOC3L2: Changed phenotypes: Brain malformation renal syndrome, MIM# 620943
Mendeliome v1.2014 THAP11 Zornitza Stark Phenotypes for gene: THAP11 were changed from Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related to Methylmalonic aciduria, cblC type-like, MIM# 620940; Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Mendeliome v1.2013 THAP11 Zornitza Stark edited their review of gene: THAP11: Changed phenotypes: Methylmalonic aciduria, cblC type-like, MIM# 620940, Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Mendeliome v1.2013 PHKG2 Sangavi Sivagnanasundram reviewed gene: PHKG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 6962066, 8896567, 9384616, 35549678, 24389071, 25266922, 21646031; Phenotypes: glycogen storage disease IXc MONDO:0013091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2013 PIH1D3 Sangavi Sivagnanasundram reviewed gene: PIH1D3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28041644, 28176794, 32170493, 38051289, 33106461, 38408845, 33635866; Phenotypes: ciliary dyskinesia, primary, 36, X-linked MONDO:0010517; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.2013 IFIH1 Sangavi Sivagnanasundram reviewed gene: IFIH1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 24686847, 24995871, 25620204, 30219631, 31898846; Phenotypes: IFIH1-related type 1 interferonopathy MONDO:0700262; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2013 IRF4 Sangavi Sivagnanasundram reviewed gene: IRF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 36662884, 36917008, 29537367, 29408330; Phenotypes: combined immunodeficiency MONDO:0015131; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2013 AICDA Sangavi Sivagnanasundram reviewed gene: AICDA: Rating: GREEN; Mode of pathogenicity: None; Publications: 22992148, 12910268, 14564357, 15893695, 32423680, 35570134, 17560278; Phenotypes: hyper-IgM syndrome type 2 MONDO:0011528; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.2013 RBSN Zornitza Stark Phenotypes for gene: RBSN were changed from intellectual disability, MONDO:0001071, RBSN-related to Kariminejad-Reversade neurodevelopmental syndrome, MIM# 620937
Mendeliome v1.2012 RBSN Zornitza Stark edited their review of gene: RBSN: Changed phenotypes: Kariminejad-Reversade neurodevelopmental syndrome, MIM# 620937
Mendeliome v1.2012 B2M Bryony Thompson Mode of inheritance for gene: B2M was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.2011 B2M Bryony Thompson reviewed gene: B2M: Rating: GREEN; Mode of pathogenicity: None; Publications: 22693999, 37223323, 24014031, 35575118, 32875920; Phenotypes: variant ABeta2M amyloidosis MONDO:0017810; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.2011 RNU2-2P Zornitza Stark Marked gene: RNU2-2P as ready
Mendeliome v1.2011 RNU2-2P Zornitza Stark Gene: rnu2-2p has been classified as Green List (High Evidence).
Mendeliome v1.2011 RNU2-2P Zornitza Stark Classified gene: RNU2-2P as Green List (high evidence)
Mendeliome v1.2011 RNU2-2P Zornitza Stark Gene: rnu2-2p has been classified as Green List (High Evidence).
Mendeliome v1.2010 RNU2-2P Zornitza Stark gene: RNU2-2P was added
gene: RNU2-2P was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU2-2P was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RNU2-2P were set to https://www.medrxiv.org/content/10.1101/2024.09.03.24312863v1
Phenotypes for gene: RNU2-2P were set to Neurodevelopmental disorder, MONDO:0700092, RNU2-2P-related
Review for gene: RNU2-2P was set to GREEN
Added comment: 15 individuals reported with de novo, recurrent variants in this gene at nucleotide positions 4 and 35. The disorder is characterized by intellectual disability, neurodevelopmental delay, autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases display a severe and complex seizure phenotype.
Sources: Literature
Mendeliome v1.2009 PNKP Shakira Heerah reviewed gene: PNKP: Rating: GREEN; Mode of pathogenicity: None; Publications: 31436889, 31707899, 20118933, 23224214, 29243230, 2578773, 27066567; Phenotypes: Ataxia-oculomotor apraxia 4, Microcephaly, seizures, and developmental delay, Charcot-Marie-Tooth disease, type 2B2; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.2009 NFU1 Zornitza Stark Phenotypes for gene: NFU1 were changed from Multiple mitochondrial dysfunctions syndrome 1, MIM# 605711 to Multiple mitochondrial dysfunctions syndrome 1, MIM# 605711; Spastic paraplegia 93, autosomal recessive, MIM# 620938
Mendeliome v1.2008 NFU1 Zornitza Stark edited their review of gene: NFU1: Changed phenotypes: Multiple mitochondrial dysfunctions syndrome 1, MIM# 605711, Spastic paraplegia 93, autosomal recessive, MIM# 620938
Mendeliome v1.2008 SGMS1 Bryony Thompson Marked gene: SGMS1 as ready
Mendeliome v1.2008 SGMS1 Bryony Thompson Gene: sgms1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2008 SGMS1 Bryony Thompson Classified gene: SGMS1 as Amber List (moderate evidence)
Mendeliome v1.2008 SGMS1 Bryony Thompson Gene: sgms1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2007 REPS2 Bryony Thompson Marked gene: REPS2 as ready
Mendeliome v1.2007 REPS2 Bryony Thompson Gene: reps2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2007 TTL Bryony Thompson Marked gene: TTL as ready
Mendeliome v1.2007 TTL Bryony Thompson Gene: ttl has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2007 REPS2 Bryony Thompson Classified gene: REPS2 as Amber List (moderate evidence)
Mendeliome v1.2007 REPS2 Bryony Thompson Gene: reps2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2006 TTL Bryony Thompson Classified gene: TTL as Amber List (moderate evidence)
Mendeliome v1.2006 TTL Bryony Thompson Gene: ttl has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2005 MRPL42 Bryony Thompson Marked gene: MRPL42 as ready
Mendeliome v1.2005 MRPL42 Bryony Thompson Gene: mrpl42 has been classified as Red List (Low Evidence).
Mendeliome v1.2005 MRPL42 Bryony Thompson Classified gene: MRPL42 as Red List (low evidence)
Mendeliome v1.2005 MRPL42 Bryony Thompson Gene: mrpl42 has been classified as Red List (Low Evidence).
Mendeliome v1.2004 MED16 Bryony Thompson Marked gene: MED16 as ready
Mendeliome v1.2004 MED16 Bryony Thompson Gene: med16 has been classified as Green List (High Evidence).
Mendeliome v1.2004 MED16 Bryony Thompson Classified gene: MED16 as Green List (high evidence)
Mendeliome v1.2004 MED16 Bryony Thompson Gene: med16 has been classified as Green List (High Evidence).
Mendeliome v1.2003 GPN2 Bryony Thompson Marked gene: GPN2 as ready
Mendeliome v1.2003 GPN2 Bryony Thompson Gene: gpn2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2003 GPN2 Bryony Thompson Classified gene: GPN2 as Amber List (moderate evidence)
Mendeliome v1.2003 GPN2 Bryony Thompson Gene: gpn2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2002 FKBP4 Bryony Thompson Marked gene: FKBP4 as ready
Mendeliome v1.2002 FKBP4 Bryony Thompson Gene: fkbp4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2002 FKBP4 Bryony Thompson Classified gene: FKBP4 as Amber List (moderate evidence)
Mendeliome v1.2002 FKBP4 Bryony Thompson Gene: fkbp4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2001 EIF3I Bryony Thompson Marked gene: EIF3I as ready
Mendeliome v1.2001 EIF3I Bryony Thompson Gene: eif3i has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2001 EIF3I Bryony Thompson Classified gene: EIF3I as Amber List (moderate evidence)
Mendeliome v1.2001 EIF3I Bryony Thompson Gene: eif3i has been classified as Amber List (Moderate Evidence).
Mendeliome v1.2000 DNAH17 Bryony Thompson Marked gene: DNAH17 as ready
Mendeliome v1.2000 DNAH17 Bryony Thompson Gene: dnah17 has been classified as Green List (High Evidence).
Mendeliome v1.2000 DNAH17 Bryony Thompson Classified gene: DNAH17 as Green List (high evidence)
Mendeliome v1.2000 DNAH17 Bryony Thompson Gene: dnah17 has been classified as Green List (High Evidence).
Mendeliome v1.1999 CEP76 Bryony Thompson Marked gene: CEP76 as ready
Mendeliome v1.1999 CEP76 Bryony Thompson Gene: cep76 has been classified as Green List (High Evidence).
Mendeliome v1.1999 CEP76 Bryony Thompson Classified gene: CEP76 as Green List (high evidence)
Mendeliome v1.1999 CEP76 Bryony Thompson Gene: cep76 has been classified as Green List (High Evidence).
Mendeliome v1.1998 CEP76 Mark Cleghorn gene: CEP76 was added
gene: CEP76 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: CEP76 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CEP76 were set to complex neurodevelopmental disorder MONDO:0100038; Joubert syndrome; Bardet-Biedl syndrome; retinitis pigmentosa
Penetrance for gene: CEP76 were set to unknown
Review for gene: CEP76 was set to GREEN
Added comment: Erica Davis, Stanley Manne Children’s research institute, Chicago
ESHG presentation 4/6/24, unpublished

CEP76 associated with syndromic ciliopathy

CEP76 localizes to centrioles and basal body primary cilia
Role in normal centriolar duplication

Index case
Bardet Biedl syndrome
Compound heterozygous pLoF variants in CEP76

Via Gene matcher
7 cases in 7 families- biallelic CEP76 and various clinical features within ciliopathy spectrum:
Obesity
Ocular phenotype
Structural brain anomalies
Renal?

3/7 families clinical Dx Joubert syndrome
1/7 BBS
1/7 GDD/ID NOS
2/7 retinitis pigmentosa (1 of these with learning difficulties)

Mixture of biallelic pLOF and missense variant

CEP76 knockout zebrafish model shows retinal phenotype w photoreceptor loss, similar to homozygous known BBS4 pathogenic variant

Cell based fx studies with missense variants above, consistent with centriolar duplication dysfunction
Sources: Other
Mendeliome v1.1998 EIF3I Mark Cleghorn gene: EIF3I was added
gene: EIF3I was added to Mendeliome. Sources: Other
Mode of inheritance for gene: EIF3I was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: EIF3I were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: EIF3I were set to unknown
Review for gene: EIF3I was set to AMBER
Added comment: Marcello Scala, Genoa
ESHG presentation 4/6/24, unpublished

De novo EIF3I missense variants as a cause for novel NDD syndrome

EIF3 complex involved in regulating initiation of mRNA translation
Negative regulator of the TGF beta pathway

8 individuals from 8 families
Mod/severe GDD or ID
Short stature
Midline brain anomalies (hypoplasia/agenesis of corpus callosum and pituitary hypoplasia)
Frontal bossing, hypertelorism, long philtrum
All w rare de novo missense variants in EIF3I, clustering within highly conserved WD repeats

Functional studies
Transfected HEK293 cell studies suggested EIF3I protein from variant alleles (from patients above) had disrupted interaction with other EIF subunits, and cells had reduced protein synthesis overall
No animal models
Sources: Other
Mendeliome v1.1998 MRPL42 Mark Cleghorn gene: MRPL42 was added
gene: MRPL42 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: MRPL42 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MRPL42 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: MRPL42 were set to unknown
Review for gene: MRPL42 was set to RED
Added comment: Bjorn Fischer-Zirnsak, Charite Berlin
ESHG presentation 4/6/24, unpublished

++ supportive functional data (on patient-derived cells) presented, but only 1 case

Biallelic MRPL42 LoF with lethal mitochondrial disease

Index case, born to consanguineous parents
Small
Hypotonia
Seizures
Conductive hearing impairment
CV: hypertrophic RV, small VSD
Hepatomegaly
Lactic acidosis

Homozygous MRPL42: c.219+6T>A (spliceAI 0.83 donor loss)
RNASeq and RT-PCR supportive of aberrant splicing resulting in out of frame exon 4 skipping
Sources: Other
Mendeliome v1.1998 MED16 Mark Cleghorn gene: MED16 was added
gene: MED16 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: MED16 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MED16 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: MED16 was set to GREEN
Added comment: Charlotte Guillouet, Imagine institute Paris
ESHG presentation 4/6/24, unpublished

MED16 is part of tail of ‘mediator complex’
Plays a role in enhancer/promotor regions

Disruptive variants in other genes encoding proteins within this mediator complex (MED11/12/12/17/20, CDK8) are assoc w neurodevelopmental/neurodegenerative disorders

Cases
index family
Sibs (M/F) to consanguineous parents w NDD/mod ID, tetralogy of Fallot or VSD, bilat deafness, micrognathia, malar hypoplasia, dental AbN, pre auricular tags, hypoplastic nails, brachydactly
WES: biallelic MED16 p.Asp217Asn

Via genematcher
16 families total, 22 individuals, homozygous or compound het rare MED16 variants
Mixture of pLoF and missense variants

Motor delay in 16/17
DD or ID in 17/17
Speech delay in 15/15
6/19 ToF
7/19 other septal/aortic defects
6/18 deafness
11/18 microretrognathia
6/17 cleft palate
8/19 preauricular tags
9/20 puffy eyelids
12/20 nasal dysplasia (most commonly short columella w bulbous nasal tip)
7/20 corpus callosum anomalies

Not clear that functional work recapitulated phenotype as yet?
Immunofluroescence on HeLa cells transfected with variants observed ?conclusion
MED16 knockout mouse > growth delay, pre weaning lethality
MED16 knockout zebrafish > reduced body length, early death, no obvious craniofacial phenotype
Sources: Other
Mendeliome v1.1998 GPN2 Mark Cleghorn gene: GPN2 was added
gene: GPN2 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: GPN2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GPN2 were set to complex neurodevelopmental disorder MONDO:0100038; Perrault syndrome
Penetrance for gene: GPN2 were set to unknown
Review for gene: GPN2 was set to AMBER
Added comment: GPN2
ESHG talk 2/6/24, unpublished
Thomas Smith, University of Manchester

Biallelic GPN2 proposed to cause Perrault syndrome (SNHL, ovarian dysfunction, NDD)
RNA polymerase assembly factor

4 families (14 affected individuals) w biallalic GPN2 rare missense variants
Segregated w phenotype
Fam 2 and 3 may be distantly related (leaving 3 distinct kindreds)

Clinical features
13/14 SNHL
3/4 families all females of adolescent age or older had primary ovarian insufficiency
4/4 GDD, ataxia (no data on family w 10 affected indiv.)

Some functional work, not conclusive
Sources: Other
Mendeliome v1.1998 FKBP4 Mark Cleghorn gene: FKBP4 was added
gene: FKBP4 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: FKBP4 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: FKBP4 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: FKBP4 were set to unknown
Review for gene: FKBP4 was set to AMBER
Added comment: Rebecca Yarwood, University of Manchester
ESHG presentation 4/6/24, unpublished

Bilalleic FKBP4 w NDD + DSD
Protein has functions in hormone receptor trafficking
FKPB4 highly expressed in stem cell and progenitor cells in gonad and neuronal degeneration

Index case
Severe GDD
abN external genitalia
CV AbN
FBBP4 p.E196*

Via GeneMatcher
7 families (12 individuals)

12/12 severe GDD/ID
9/10 microcephaly
11/12 external genital abnormalities (details not provided)

All w homozygous pLoF variants (mixture of canonical splice, frameshift, nonsense)
Sources: Other
Mendeliome v1.1998 SGMS1 Mark Cleghorn gene: SGMS1 was added
gene: SGMS1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: SGMS1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SGMS1 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: SGMS1 was set to AMBER
Added comment: SGMS1
Johannes Kopp, Charite Berlin
ESHG presentation 4/6/24, unpublished

Biallelic SGMS1 with novel metabolic disorder

Only 2 families (3 cases) reported
NDD, AbN cerebral myelination, SNHL, ichthyosis

Homozygous or compound het SGMS1 missense

Functional work to support role of SGMS1 in sphingolipid metabolism
Sources: Other
Mendeliome v1.1998 CAPN3 Sangavi Sivagnanasundram reviewed gene: CAPN3: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: muscular dystrophy, limb-girdle, autosomal dominant MONDO:0015151, autosomal recessive limb-girdle muscular dystrophy MONDO:0015152; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.1998 BVES Sangavi Sivagnanasundram reviewed gene: BVES: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: autosomal recessive limb-girdle muscular dystrophy MONDO:0015152; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1998 PTCRA Zornitza Stark Phenotypes for gene: PTCRA were changed from Autoinflammatory syndrome, MONDO:0019751, PTCRA-related to Immunodeficiency 126, MIM# 620931
Mendeliome v1.1997 PTCRA Zornitza Stark edited their review of gene: PTCRA: Changed phenotypes: Immunodeficiency 126, MIM# 620931
Mendeliome v1.1997 ZNRF3 Bryony Thompson Marked gene: ZNRF3 as ready
Mendeliome v1.1997 ZNRF3 Bryony Thompson Gene: znrf3 has been classified as Green List (High Evidence).
Mendeliome v1.1997 ZNRF3 Bryony Thompson Classified gene: ZNRF3 as Green List (high evidence)
Mendeliome v1.1997 ZNRF3 Bryony Thompson Gene: znrf3 has been classified as Green List (High Evidence).
Mendeliome v1.1996 ZNRF3 Bryony Thompson gene: ZNRF3 was added
gene: ZNRF3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNRF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZNRF3 were set to 39168120
Phenotypes for gene: ZNRF3 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: ZNRF3 was set to GREEN
Added comment: 12 individuals with ZNRF3 variants and various phenotypes. 8 individuals with de novo missense and neurodevelopment disorders (NDD), including cluster of variants in the RING ligase domain with macrocephalic NDD. Plus 4 individuals from 3 families with de novo truncating or de novo/inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. Overall, 4 individuals had congenital heart defects and 2 had microcephaly. Also, supporting in vitro functional assays.
Sources: Literature
Mendeliome v1.1995 RFC4 Chirag Patel Classified gene: RFC4 as Green List (high evidence)
Mendeliome v1.1995 RFC4 Chirag Patel Gene: rfc4 has been classified as Green List (High Evidence).
Mendeliome v1.1994 ATP6V1C1 Zornitza Stark Marked gene: ATP6V1C1 as ready
Mendeliome v1.1994 ATP6V1C1 Zornitza Stark Gene: atp6v1c1 has been classified as Red List (Low Evidence).
Mendeliome v1.1994 ATP6V1C1 Zornitza Stark Phenotypes for gene: ATP6V1C1 were changed from to neurodevelopmental disorder MONDO:0700092, ATP6V1C1-related
Mendeliome v1.1993 C12orf66 Zornitza Stark Marked gene: C12orf66 as ready
Mendeliome v1.1993 C12orf66 Zornitza Stark Gene: c12orf66 has been classified as Green List (High Evidence).
Mendeliome v1.1993 C12orf66 Zornitza Stark Classified gene: C12orf66 as Green List (high evidence)
Mendeliome v1.1993 C12orf66 Zornitza Stark Gene: c12orf66 has been classified as Green List (High Evidence).
Mendeliome v1.1992 RFC4 Chirag Patel gene: RFC4 was added
gene: RFC4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RFC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RFC4 were set to PMID: 39106866
Phenotypes for gene: RFC4 were set to RFC4-related multisystem disorder
Review for gene: RFC4 was set to GREEN
gene: RFC4 was marked as current diagnostic
Added comment: 9 affected individuals (aged birth to 47yrs) from 8 unrelated families with a multisystem disorder. Clinical features included: muscle weakness/myopathy (9/9), motor incoordination/gait disturbance (8/8), delayed gross motor development (6/9), dysarthria (5/5), peripheral neuropathy (3/3 adults), bilateral sensorineural hearing impairment (6/9), decreased body weight (8/9), short stature (5/9), microcephaly (4/9), respiratory issues/insufficiency (6/9), cerebellar atrophy (4/9), pituitary hypoplasia (3/9).

WES or WGS identified biallelic loss-of-function variants in RFC4 (3 frameshift, 2 splice site, 1 single AA duplication, 2 single AA deletions, 2 missense), and almost all are likely to disrupt the C-terminal domain indispensable for Replication factor C (RFC) complex formation. All variants segregated with the disease.

The RFC complex (with 5 subunits) is central to process of regulation of DNA replication, and it loads proliferating cell nuclear antigen onto DNA to facilitate the recruitment of replication and repair proteins and enhance DNA polymerase processivity. RFC1 is associated with CANVAS but the contributions of RFC2-5 subunits on human Mendelian disorders is unknown.

Analysis of a previously determined cryo-EM structure of RFC bound to proliferating cell nuclear antigen suggested that the variants disrupt interactions within RFC4 and/or destabilize the RFC complex. Cellular studies using RFC4-deficient HeLa cells and primary fibroblasts demonstrated decreased RFC4 protein, compromised stability of the other RFC complex subunits, and perturbed RFC complex formation. Additionally, functional studies of the RFC4 variants affirmed diminished RFC complex formation, and cell cycle studies suggested perturbation of DNA replication and cell cycle progression.
Sources: Literature
Mendeliome v1.1991 COQ8B Zornitza Stark Phenotypes for gene: COQ8B were changed from Nephrotic syndrome, type 9 MIM#615573 to Nephrotic syndrome, type 9 MIM#615573; Retinitis pigmentosa MONDO:0019200
Mendeliome v1.1990 COQ8B Zornitza Stark Publications for gene: COQ8B were set to 24270420
Mendeliome v1.1989 SF3B1 Zornitza Stark Classified gene: SF3B1 as Green List (high evidence)
Mendeliome v1.1989 SF3B1 Zornitza Stark Gene: sf3b1 has been classified as Green List (High Evidence).
Mendeliome v1.1988 SF3B1 Zornitza Stark Marked gene: SF3B1 as ready
Mendeliome v1.1988 SF3B1 Zornitza Stark Gene: sf3b1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1988 SF3B1 Zornitza Stark Classified gene: SF3B1 as Amber List (moderate evidence)
Mendeliome v1.1988 SF3B1 Zornitza Stark Gene: sf3b1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1987 JPH1 Zornitza Stark Marked gene: JPH1 as ready
Mendeliome v1.1987 JPH1 Zornitza Stark Gene: jph1 has been classified as Green List (High Evidence).
Mendeliome v1.1987 JPH1 Zornitza Stark Classified gene: JPH1 as Green List (high evidence)
Mendeliome v1.1987 JPH1 Zornitza Stark Gene: jph1 has been classified as Green List (High Evidence).
Mendeliome v1.1986 MED22 Zornitza Stark Marked gene: MED22 as ready
Mendeliome v1.1986 MED22 Zornitza Stark Gene: med22 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1986 MED22 Zornitza Stark Classified gene: MED22 as Amber List (moderate evidence)
Mendeliome v1.1986 MED22 Zornitza Stark Gene: med22 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1985 LARP1 Zornitza Stark Marked gene: LARP1 as ready
Mendeliome v1.1985 LARP1 Zornitza Stark Gene: larp1 has been classified as Green List (High Evidence).
Mendeliome v1.1985 LARP1 Zornitza Stark Classified gene: LARP1 as Green List (high evidence)
Mendeliome v1.1985 LARP1 Zornitza Stark Gene: larp1 has been classified as Green List (High Evidence).
Mendeliome v1.1984 PNPLA8 Zornitza Stark Phenotypes for gene: PNPLA8 were changed from Mitochondrial myopathy with lactic acidosis (MIM#251950), AR to Complex neurodevelopmental disorder, MONDO:0100038, PNPLA8-related; Mitochondrial myopathy with lactic acidosis (MIM#251950), AR
Mendeliome v1.1983 SPARCL1 Zornitza Stark Marked gene: SPARCL1 as ready
Mendeliome v1.1983 SPARCL1 Zornitza Stark Gene: sparcl1 has been classified as Red List (Low Evidence).
Mendeliome v1.1983 SPARCL1 Zornitza Stark gene: SPARCL1 was added
gene: SPARCL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPARCL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPARCL1 were set to 39169229
Phenotypes for gene: SPARCL1 were set to Corneal dystrophy, MONDO:0018102
Review for gene: SPARCL1 was set to RED
Added comment: 8 affected individuals with corneal dystrophy from 1 family (3 generations). Affected individuals had diffuse central stromal opacity, with reduced visual acuity in older family members. Histopathology of affected cornea tissue revealed mild stromal textural alterations with alcianophilic deposits.

WGS from 4 affected individuals in family identified a novel heterozygous missense variant in exon 4 of SPARCL1 (c.334G > A; p.(Glu112Lys)) which segregated with disease.

SPARC-like protein 1 (SPARCL1) is a secreted matricellular protein involved in cell migration, cell adhesion, tissue repair, and remodelling. SPARCL1 has been shown to regulate decorin. Heterozygous variants in DCN, encoding decorin, cause autosomal dominant congenital stromal corneal dystrophy, suggesting a common pathogenic pathway. Immunohistochemistry showed the level of decorin was significantly decreased in the corneal stroma of the affected tissue, and SPARCL1 appeared to be retained in the epithelium.
Sources: Literature
Mendeliome v1.1982 NDUFA7 Zornitza Stark Phenotypes for gene: NDUFA7 were changed from to Optic atrophy, MONDO:0003608, NDUFA7-related
Mendeliome v1.1981 NDUFA7 Zornitza Stark Mode of inheritance for gene: NDUFA7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1980 NDUFA7 Zornitza Stark edited their review of gene: NDUFA7: Changed rating: RED
Mendeliome v1.1980 NDUFA7 Zornitza Stark reviewed gene: NDUFA7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Optic atrophy, MONDO:0003608, NDUFA7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1980 ABL1 Sangavi Sivagnanasundram reviewed gene: ABL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39155385, 38743093; Phenotypes: Human ABL1 Deficiency Syndrome (HADS); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1980 GMPPB Sangavi Sivagnanasundram reviewed gene: GMPPB: Rating: GREEN; Mode of pathogenicity: None; Publications: 27147698; Phenotypes: myopathy caused by variation in GMPPB MONDO:0700084; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1980 LARP1 Sangavi Sivagnanasundram gene: LARP1 was added
gene: LARP1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: LARP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LARP1 were set to 39182167
Phenotypes for gene: LARP1 were set to Neurodevelopmental disorder; MONDO:0700092
Review for gene: LARP1 was set to GREEN
Added comment: Seven unrelated probands (6 males and 1 female) with ASD or another variable NDD phenotype (ID, hypotonia, motor delay and/or ASD). Variants were showed to be de novo null variants or missense variants that resulted in haploinsufficiency.

Ex vivo (knockout CRISPR-Cas9) functional assay using lymphoblasts that was collected and immortilised from one proband was conducted to assess the functional impact of the LARP1 variant. The results showed a reduction in protein compared to WT causing reduced rates of aerobic respiration and glycolysis.
Sources: Other
Mendeliome v1.1980 PNPLA8 Chirag Patel edited their review of gene: PNPLA8: Added comment: Cohort analysis of clinical features of new and previously reported individuals with biallelic PNPLA8 variants (25 affected individuals across 20 families). They showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. Complete loss of PNPLA8 was associated with the more profound end of the spectrum.

Using cerebral organoids generated from human induced pluripotent stem cells, they found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. They show that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development.; Set current diagnostic: yes
Mendeliome v1.1980 PNPLA8 Chirag Patel reviewed gene: PNPLA8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 39082157; Phenotypes: PNPLA8-related neurological diseases; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1980 MED22 Mark Cleghorn gene: MED22 was added
gene: MED22 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: MED22 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MED22 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: MED22 were set to unknown
Review for gene: MED22 was set to AMBER
Added comment: ESHG talk 2/6/24, unpublished
Elisa Cali, UCL

Recurrent homozygous MED22:c.397_399del (p.Glu133del) inframe variant in 8 individuals from 6 families w progressive NDD, microcepahly, cerebellar atrophy, dystonia, seizures

Rare in gnomad v4.1 (9 het alleles, no homozygotes)

Functional work on patient fibroblasts: quantity of protein comparable to controls, did not mentioned assays of protein function (?mechanism proposed)
Drosophilia heterozygous model with equivalent of p.Glu133del variant: structural anomalies, less movements, all died prior to pupae stage
Zebrafish: MED22 mutants less mobile, died prior to adulthood, reduced brain size
Sources: Other
Mendeliome v1.1980 TMEM216 Zornitza Stark Phenotypes for gene: TMEM216 were changed from Joubert syndrome 2, MIM# 608091; MONDO:0011963; Meckel syndrome 2, MIM# 603194; MONDO:0011296 to Joubert syndrome 2, MIM# 608091; MONDO:0011963; Meckel syndrome 2, MIM# 603194; MONDO:0011296; Retinitis pigmentosa, MONDO:0019200, TMEM216-related
Mendeliome v1.1979 TMEM216 Zornitza Stark Publications for gene: TMEM216 were set to 20036350; 20512146
Mendeliome v1.1978 TMEM216 Zornitza Stark Tag founder tag was added to gene: TMEM216.
Tag UTR tag was added to gene: TMEM216.
Mendeliome v1.1978 TMEM216 Zornitza Stark edited their review of gene: TMEM216: Added comment: PMID 39191256: Two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]) found in individuals of South Asian and African ancestry, respectively.

This included 71 homozygotes and 3 mixed heterozygotes in trans with a predicted loss-of-function allele. Haplotype analysis showed single-nucleotide variants (SNVs) common across families, suggesting ancestral alleles within the two distinct ethnic populations.

Clinical phenotype analysis of 62 available individuals from 49 families indicated a similar clinical presentation with night blindness in the first decade and progressive peripheral field loss thereafter. No evident systemic ciliopathy features were noted.

Functional characterization of these variants by luciferase reporter gene assay showed reduced promotor activity.; Changed publications: 20036350, 20512146, 39191256; Changed phenotypes: Joubert syndrome 2, MIM# 608091, MONDO:0011963, Meckel syndrome 2, MIM# 603194, MONDO:0011296, Retinitis pigmentosa, MONDO:0019200, TMEM216-related
Mendeliome v1.1978 JPH1 Sangavi Sivagnanasundram changed review comment from: 4 unrelated probands presented with congenital myopathy with prominent facial and ocular involvement. All individuals had presence of 4 different LoF variants identified in JPH1.

p.(Asp125Thrfs*30), p.(Tyr118*), p.(Leu580Trpfs*16) and p.(Glu504Serfs*3) - all variants were absent from gnomADv4.1
Sources: Other; to: 4 unrelated probands presented with congenital myopathy with facial weakness and ocular involvement. All individuals had presence of 4 different LoF variants identified in JPH1.

p.(Asp125Thrfs*30), p.(Tyr118*), p.(Leu580Trpfs*16) and p.(Glu504Serfs*3) - all variants were absent from gnomADv4.1
Sources: Other
Mendeliome v1.1978 JPH1 Sangavi Sivagnanasundram gene: JPH1 was added
gene: JPH1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: JPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JPH1 were set to 39209426
Phenotypes for gene: JPH1 were set to Congenital myopathy MONDO:0019952
Review for gene: JPH1 was set to GREEN
Added comment: 4 unrelated probands presented with congenital myopathy with prominent facial and ocular involvement. All individuals had presence of 4 different LoF variants identified in JPH1.

p.(Asp125Thrfs*30), p.(Tyr118*), p.(Leu580Trpfs*16) and p.(Glu504Serfs*3) - all variants were absent from gnomADv4.1
Sources: Other
Mendeliome v1.1978 PLEC Zornitza Stark Phenotypes for gene: PLEC were changed from ?Epidermolysis bullosa simplex with nail dystrophy, MIM# 616487; Epidermolysis bullosa simplex with muscular dystrophy, MIM# 226670; Epidermolysis bullosa simplex with pyloric atresia, MIM# 612138; Epidermolysis bullosa simplex, Ogna type MIM#131950; Muscular dystrophy, limb-girdle, autosomal recessive 17, MIM# 613723 to Epidermolysis bullosa simplex with nail dystrophy, MIM# 616487; Epidermolysis bullosa simplex with muscular dystrophy, MIM# 226670; Epidermolysis bullosa simplex with pyloric atresia, MIM# 612138; Epidermolysis bullosa simplex, Ogna type MIM#131950; Muscular dystrophy, limb-girdle, autosomal recessive 17, MIM# 613723; Progressive familial intrahepatic cholestasis, MONDO:0015762, PLEC-related
Mendeliome v1.1977 PLEC Zornitza Stark Publications for gene: PLEC were set to 22144912
Mendeliome v1.1976 PLEC Zornitza Stark reviewed gene: PLEC: Rating: AMBER; Mode of pathogenicity: None; Publications: 39168815; Phenotypes: Progressive familial intrahepatic cholestasis, MONDO:0015762, PLEC-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1976 SF3B1 Mark Cleghorn gene: SF3B1 was added
gene: SF3B1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: SF3B1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SF3B1 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: SF3B1 were set to unknown
Review for gene: SF3B1 was set to AMBER
Added comment: SF3B1
Delphine Bernard, University of Brest
ESHG talk 2/6/24, unpublished

De novo germline SF3B1 variants, proposed spliceosomopathy/NDD gene

SF3B1 is an RNA binding protein that stabilizes the U2 snRNP complex at branchpoint sequences
Somatic SF3B1 missense commonly occur in haematological malignancy (K700E recurrent)

25 patients with syndromic NDD + de novo heterozygous rare SF3B1 variants identified on WES, genematcher
13 missense (incl recurrent xxx and xxx) within HEAT domain
5 nonsense
4 splicing
1 frameshift

Patients w missense variants may have more severe phenotype incl mircocepahly, palate anomalies, cerebral anomalies, GI/cardiac anomalies

Cellular models of missense variants: erythroleukaemia K562, HEK293T
Suggest missense variants do not cause loss of function, but increase exon skipping and alternative 3’ splice site use
Sources: Other
Mendeliome v1.1976 GBF1 Ain Roesley reviewed gene: GBF1: Rating: RED; Mode of pathogenicity: None; Publications: 39110251; Phenotypes: autosomal dominant cataract MONDO:0022672, GBF1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1976 TLN1 Ain Roesley reviewed gene: TLN1: Rating: AMBER; Mode of pathogenicity: None; Publications: 39163585; Phenotypes: idiopathic spontaneous coronary artery dissection MONDO:0007385; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1976 COQ8B Bryony Thompson reviewed gene: COQ8B: Rating: GREEN; Mode of pathogenicity: None; Publications: 39226897, 25967120; Phenotypes: Retinitis pigmentosa MONDO:0019200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1976 C12orf66 Mark Cleghorn gene: C12orf66 was added
gene: C12orf66 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: C12orf66 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: C12orf66 were set to complex neurodevelopmental disorder MONDO:0100038
Penetrance for gene: C12orf66 were set to unknown
Review for gene: C12orf66 was set to AMBER
Added comment: KICS2 (previously known as C12ORF66)
Rebecca Buchert, Universitatklinikum Tubingen
ESHG talk 2/6/24, unpublished

Proposed ID + epilepsy gene

8 families w 11 affected individuals
Phenotypes: 11/11 ID, 9/11 epilepsy, 3/11 hearing impairment
3/8 homozygous missense variants (p.Asp296Glu, p.Tyr393Cys, p.Tyr393Cys), all highly conserved
1/8 compound het PTC (p.Lys262*) with 1.1Mb deletion
4/8 homozygous PTC (p.Glu3*, p.Gly79Valfs*18, p.Gly79Valfs*18, p.Lys260Asnfs*18)

Gene appears to be involved in mTOR pathway, and cilia function
mTORC1 activity in CRISPR-HEK293T cells – reduced activity in cells w variants above

Zebrafish model: otolith defects, ciliary dysfunction
?not clear that this truly mimics phenotype observed in patient cohort described
Sources: Other
Mendeliome v1.1976 MYBBP1A Zornitza Stark Marked gene: MYBBP1A as ready
Mendeliome v1.1976 MYBBP1A Zornitza Stark Gene: mybbp1a has been classified as Green List (High Evidence).
Mendeliome v1.1976 MYBBP1A Zornitza Stark Classified gene: MYBBP1A as Green List (high evidence)
Mendeliome v1.1976 MYBBP1A Zornitza Stark Gene: mybbp1a has been classified as Green List (High Evidence).
Mendeliome v1.1975 MYBBP1A Zornitza Stark gene: MYBBP1A was added
gene: MYBBP1A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYBBP1A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYBBP1A were set to 39191491; 28425981
Phenotypes for gene: MYBBP1A were set to Hydrops fetalis, MONDO:0015193, MYBBP1A-related
Review for gene: MYBBP1A was set to GREEN
Added comment: Three unrelated fetuses with bi-allelic variants in this gene and severe hydrops.
Sources: Literature
Mendeliome v1.1974 ATP6V1C1 Ain Roesley edited their review of gene: ATP6V1C1: Changed phenotypes: neurodevelopmental disorder MONDO:0700092, ATP6V1C1-related
Mendeliome v1.1974 ATP6V1C1 Ain Roesley gene: ATP6V1C1 was added
gene: ATP6V1C1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP6V1C1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP6V1C1 were set to 39210597
Review for gene: ATP6V1C1 was set to AMBER
gene: ATP6V1C1 was marked as current diagnostic
Added comment: 1x de novo missense p.Glu289Lys (absent in v4 gnomad). Manual inspection of IGV found the dad was mosaic 7% VAF and he shared some of the clinical features (minor digit anomalies).

Some functional studies using patient fibroblasts were performed, demonstrating similar effects as known pathogenic variants in ATP6V1B2.
- lysosomal morphology
- autophagic flux dysregulation
- increased acidification of lysosome

borderline red/amber
Sources: Literature
Mendeliome v1.1973 REPS2 Mark Cleghorn gene: REPS2 was added
gene: REPS2 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: REPS2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: REPS2 were set to complex neurodevelopmental disorder MONDO:0100038; Cerebral palsy HP:0100021
Penetrance for gene: REPS2 were set to unknown
Review for gene: REPS2 was set to AMBER
Added comment: REPS2
Hao Hu, Guangzhou Women and Children’s MC
ESHG talk 1/6/24, unpublished

Proposed X-linked cerebral palsy + NDD gene

4 unrelated males with predicted deleterious hemizygous REPS2 variants, 2 PTC, 2 missense. 2 de novo, 2 maternally inherited
Phenotypes: 2 w CP + moderate ID/ASD, 2 w NDD NOS
Variants described:
c.1050_1052delGAA;p.K351del
c.1040T>C; p.I347T
c.962C>G; p.S321C
c.1736delA; p.N579Tfs*17

In vitro assay of above 4 variants suggest reduced REPS2 protein stability
Zebrafish model: REPS2 expressed in neuronal cells, REPS2 knock down have reduced motor activity and abN neuronal morphology
Mouse model hemizygous w one of above variants (not specified): reduced performance in cognitive tasks, abnormal neuronal migration pattern on post mortem examination
Mechanism may relate to dopamine signalling?
Sources: Other
Mendeliome v1.1973 TTL Mark Cleghorn gene: TTL was added
gene: TTL was added to Mendeliome. Sources: Other
Mode of inheritance for gene: TTL was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TTL were set to complex neurodevelopmental disorderMONDO:0100038
Added comment: TTL
Valentina Serpieri, University of Pavia
ESHG talk 1/6/24

FAM1 (Italy)
2 affected sisters born to consanguineous Pakistani parents
GDD, spastic tetraparesis, optic atrophy, brain anomalies resembling tubulinopathies (dysplasia of corpus callosum, basal ganglia, brainstem)
WES: homozygous TTL:c.1013G>A; p.Cys338Tyr in both affected sisters

Via genematcher
5 more families (9 individuals) w similar phenotypes and biallelic variants in TTL

FAM2 (Egypt): homozygous p.Arg46Pro
FAM3 (Egypt): homozygous p.Arg46Pro
FAM4 (Australia): homozygous p.Gln183Arg
FAM5 (France): homozygous p.Trp147*
FAM6 (Saudi Arabia): homozygous p.His243Tyr

TTL KO mice: death soon after birth, no overt malformations, but defects in organisation of cerebral layers

Functional work on patient fibroblasts
FAM1 – reduced quantity of TTL protein compared to control on Western blot, decreased function of TTL protein (increase in detyrosinated tubulin) compared to controls – infer LoF as mechanism
FAM3 – mentioned but no details
FAM4– mentioned but no details
Sources: Other
Mendeliome v1.1973 PLEKHM2 Bryony Thompson Marked gene: PLEKHM2 as ready
Mendeliome v1.1973 PLEKHM2 Bryony Thompson Gene: plekhm2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1973 PLEKHM2 Bryony Thompson Classified gene: PLEKHM2 as Amber List (moderate evidence)
Mendeliome v1.1973 PLEKHM2 Bryony Thompson Gene: plekhm2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1972 PLEKHM2 Bryony Thompson gene: PLEKHM2 was added
gene: PLEKHM2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLEKHM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLEKHM2 were set to 35862026; 26464484; 38942823; 38490981; 37349842
Phenotypes for gene: PLEKHM2 were set to Dilated cardiomyopathy MONDO:0005021
Review for gene: PLEKHM2 was set to AMBER
Added comment: 2 unrelated families reported with DCM and supporting functional evidence
PMID: 35862026 - 21 yo with DCM with bialleic PLEKHM2 variants. Loss PLEKHM2 expression was found in the proband’s myocardial tissue

PMID: 26464484 - a homozygous frameshift variant (p.Lys645AlafsTer12) segregates with early-onset (adolescent) DCM and LVNC in a large consanguineous Bedouin family

PMID: 38942823 - murine model suggests Plekhm2 acts as an autophagy modulator in cardiofibroblasts

PMID: 38490981, 37349842 - supportive PLEKHM2 knockout iPSC-cardiomyocyte models
Sources: Literature
Mendeliome v1.1971 FLT3LG Zornitza Stark Phenotypes for gene: FLT3LG were changed from Increased susceptibility to infections to Immunodeficiency 125, MIM# 620926
Mendeliome v1.1970 FLT3LG Zornitza Stark reviewed gene: FLT3LG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 125, MIM# 620926; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1970 GTPBP1 Zornitza Stark Phenotypes for gene: GTPBP1 were changed from Neurodevelopmental disorder (MONDO#0700092), GTPBP1-related to Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MIM# 620888
Mendeliome v1.1969 GTPBP1 Zornitza Stark reviewed gene: GTPBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, MIM# 620888; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1969 LRP1 Zornitza Stark Phenotypes for gene: LRP1 were changed from to Developmental dysplasia of the hip 3, MIM# 620690; Keratosis pilaris atrophicans MIM#604093
Mendeliome v1.1968 LRP1 Zornitza Stark Publications for gene: LRP1 were set to
Mendeliome v1.1967 LRP1 Zornitza Stark Mode of inheritance for gene: LRP1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1966 LRP1 Zornitza Stark Classified gene: LRP1 as Amber List (moderate evidence)
Mendeliome v1.1966 LRP1 Zornitza Stark Gene: lrp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1965 LRP1 Zornitza Stark reviewed gene: LRP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36067312; Phenotypes: Developmental dysplasia of the hip 3, MIM# 620690; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1965 RAB32 Zornitza Stark Phenotypes for gene: RAB32 were changed from Parkinson disease MONDO:0005180 to {Parkinson disease 26, autosomal dominant, susceptibility to}, MIM# 620923
Mendeliome v1.1964 RAB32 Zornitza Stark Publications for gene: RAB32 were set to 38614108
Mendeliome v1.1963 RAB32 Zornitza Stark Classified gene: RAB32 as Amber List (moderate evidence)
Mendeliome v1.1963 RAB32 Zornitza Stark Gene: rab32 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1962 RAB32 Zornitza Stark reviewed gene: RAB32: Rating: AMBER; Mode of pathogenicity: None; Publications: 38858457; Phenotypes: {Parkinson disease 26, autosomal dominant, susceptibility to}, MIM# 620923; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1962 VPS52 Bryony Thompson Marked gene: VPS52 as ready
Mendeliome v1.1962 VPS52 Bryony Thompson Gene: vps52 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1962 VPS52 Bryony Thompson Classified gene: VPS52 as Amber List (moderate evidence)
Mendeliome v1.1962 VPS52 Bryony Thompson Gene: vps52 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1961 VPS52 Bryony Thompson gene: VPS52 was added
gene: VPS52 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: VPS52 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: VPS52 were set to complex neurodevelopmental disorder with or without congenital anomalies MONDO:0100465
Review for gene: VPS52 was set to AMBER
Added comment: HGSA poster (P110) from Louise Bicknell's group at the University of Otago. 11 cases from 8 families (USA, NZ, Saudi Arabia) with a broad syndromic developmental delay phenotype with biallelic variants (both missense & truncating).
Sources: Other
Mendeliome v1.1960 ELMOD3 Zornitza Stark Classified gene: ELMOD3 as Red List (low evidence)
Mendeliome v1.1960 ELMOD3 Zornitza Stark Gene: elmod3 has been classified as Red List (Low Evidence).
Mendeliome v1.1959 ELMOD3 Zornitza Stark edited their review of gene: ELMOD3: Added comment: Discussed at GenCC: limited.; Changed rating: RED
Mendeliome v1.1959 CFAP57 Zornitza Stark Phenotypes for gene: CFAP57 were changed from to Spermatogenic failure 95, MIM# 620917; Van der Woude Syndrome; Primary ciliary dyskinesia
Mendeliome v1.1958 CFAP57 Zornitza Stark Publications for gene: CFAP57 were set to
Mendeliome v1.1957 CFAP57 Zornitza Stark Classified gene: CFAP57 as Green List (high evidence)
Mendeliome v1.1957 CFAP57 Zornitza Stark Gene: cfap57 has been classified as Green List (High Evidence).
Mendeliome v1.1956 CFAP57 Zornitza Stark edited their review of gene: CFAP57: Added comment: PMID 36752199: 5 individuals from three families reported with biallelic LoF variants (two homozygous variants) and spermatogenic failure. Mouse model recapitulated the phenotype.; Changed rating: GREEN; Changed publications: 21574244, 32764743, 36752199; Changed phenotypes: Spermatogenic failure 95, MIM# 620917, Van der Woude Syndrome, Primary ciliary dyskinesia
Mendeliome v1.1956 FICD Zornitza Stark Phenotypes for gene: FICD were changed from Hereditary motor neurone disease, FICD-related, MONDO:0024257 to Spastic paraplegia 92, autosomal recessive, MIM# 620911
Mendeliome v1.1955 FIG4 Zornitza Stark Marked gene: FIG4 as ready
Mendeliome v1.1955 FIG4 Zornitza Stark Gene: fig4 has been classified as Green List (High Evidence).
Mendeliome v1.1955 FIG4 Zornitza Stark Classified gene: FIG4 as Green List (high evidence)
Mendeliome v1.1955 FIG4 Zornitza Stark Gene: fig4 has been classified as Green List (High Evidence).
Mendeliome v1.1954 FIG4 Zornitza Stark gene: FIG4 was added
gene: FIG4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FIG4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FIG4 were set to 23623387; 17572665; 21705420; 24878229; 18758830; 24598713
Phenotypes for gene: FIG4 were set to Yunis-Varon syndrome - MIM#216340; Polymicrogyria with epilepsy MIM# 612691; Charcot-Marie-Tooth disease, type 4J 611228; Amyotrophic lateral sclerosis 11, MIM# 612577
Review for gene: FIG4 was set to GREEN
Added comment: Associations between biallelic variants and CMT and Yunis Varon syndrome are well established.

Limited evidence for association with brain malformations and with ALS/FTD.
Sources: Expert Review
Mendeliome v1.1953 CSNK1G1 Rylee Peters reviewed gene: CSNK1G1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 33009664; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, CSNK1G-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1953 REXO2 Zornitza Stark Marked gene: REXO2 as ready
Mendeliome v1.1953 REXO2 Zornitza Stark Gene: rexo2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1953 REXO2 Zornitza Stark Classified gene: REXO2 as Amber List (moderate evidence)
Mendeliome v1.1953 REXO2 Zornitza Stark Gene: rexo2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1952 REXO2 Zornitza Stark gene: REXO2 was added
gene: REXO2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: REXO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: REXO2 were set to 39107301
Phenotypes for gene: REXO2 were set to Type 1 interferonopathy of childhood, MONDO:0957408, REXO2-related
Review for gene: REXO2 was set to AMBER
Added comment: Female infant of Chinese ancestry, presented at 2 years of age with whole-body rash with histological features of hyperkeratosis, parakeratosis and acanthosis with elongated rete ridges, focal liquefaction and degeneration of the basal layers of epidermis, vascular proliferation in the superficial dermis, infiltration of lymphocytes and eosinophils around small blood vessels in the dermis. She has recurrent infections (frequent and severe pneumonia). Extensive functional validation demonstrating heterozygous de novo mutation (p.T132A) impairs REXO2’s ability to cleave RNA leading to activation of the dsRNA sensor MDA5 leading to a Type 1 interferonopathy.
Sources: Literature
Mendeliome v1.1951 TMEFF1 Zornitza Stark Marked gene: TMEFF1 as ready
Mendeliome v1.1951 TMEFF1 Zornitza Stark Gene: tmeff1 has been classified as Green List (High Evidence).
Mendeliome v1.1951 TMEFF1 Zornitza Stark Classified gene: TMEFF1 as Green List (high evidence)
Mendeliome v1.1951 TMEFF1 Zornitza Stark Gene: tmeff1 has been classified as Green List (High Evidence).
Mendeliome v1.1950 TMEFF1 Zornitza Stark gene: TMEFF1 was added
gene: TMEFF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TMEFF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEFF1 were set to 39048830
Phenotypes for gene: TMEFF1 were set to Hereditary susceptibility to infections, MONDO:0015979, TMEFF1-related; HSV encephalitis
Review for gene: TMEFF1 was set to GREEN
Added comment: 2 unrelated patients with severe HSV encephalitis. Functional validation showing that human TMEFF1 encodes a type I IFN-independent, cortical neuron- and CNS-intrinsic restriction factor that is effective against HSV-1 that operates by impairing the entry of HSV-1 into cortical neurons.
Sources: Literature
Mendeliome v1.1949 CSMD1 Zornitza Stark Marked gene: CSMD1 as ready
Mendeliome v1.1949 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Mendeliome v1.1949 CSMD1 Zornitza Stark Classified gene: CSMD1 as Green List (high evidence)
Mendeliome v1.1949 CSMD1 Zornitza Stark Gene: csmd1 has been classified as Green List (High Evidence).
Mendeliome v1.1948 CSMD1 Krithika Murali gene: CSMD1 was added
gene: CSMD1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CSMD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSMD1 were set to PMID:38816421
Phenotypes for gene: CSMD1 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: CSMD1 was set to GREEN
Added comment: PMID 38816421 Werren et al 2024 report 8 individuals from 6 families identified through exome sequencing and subsequent gene-sharing efforts with biallelic missense CSMD1 variants. Shared phenotypic features included: GDD, ID, microcephaly and polymicrogyria. Other features included dysmorphism, IUGR, hypotonia, arthrogryposis, seizures, opthalmological anomalies and other brain white matter anomalies Heterozygous parents were unaffected.

Loss of function is the postulated mechanism based on experimental data involving early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs).

ClinGen haploinsufficiency score of 1, however, this curation was last reviewed in 2018. This gene is within the scope of review for the ClinGen Autisim and ID GCEP.
Sources: Literature
Mendeliome v1.1947 ZSCAN10 Zornitza Stark Phenotypes for gene: ZSCAN10 were changed from syndromic disease MONDO:0002254 to Otofacial neurodevelopmental syndrome, MIM# 620910
Mendeliome v1.1946 ZSCAN10 Zornitza Stark reviewed gene: ZSCAN10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Otofacial neurodevelopmental syndrome, MIM# 620910; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1946 ACOX2 Zornitza Stark Publications for gene: ACOX2 were set to 27647924; 27884763
Mendeliome v1.1945 CLDN2 Zornitza Stark Classified gene: CLDN2 as Red List (low evidence)
Mendeliome v1.1945 CLDN2 Zornitza Stark Gene: cldn2 has been classified as Red List (Low Evidence).
Mendeliome v1.1944 CLDN2 Zornitza Stark changed review comment from: Azoospermia and nephrolithiasis: single multigenerational family reported.; to: Azoospermia and nephrolithiasis: single multigenerational family reported.

LIMITED by ClinGen.
Mendeliome v1.1944 CLDN2 Zornitza Stark changed review comment from: Pancreatitis: Numerous publications linking common variants at this locus with susceptibility to pancreatitis. KO mice do not have a pancreatic phenotype. Likely polygenic susceptibility rather than Mendelian disorder.; to: Pancreatitis: Numerous publications linking common variants at this locus with susceptibility to pancreatitis. KO mice do not have a pancreatic phenotype; have calciuria. Likely polygenic susceptibility rather than Mendelian disorder.
Mendeliome v1.1944 CLDN2 Zornitza Stark changed review comment from: Azoospermia: single multigenerational family reported.; to: Azoospermia and nephrolithiasis: single multigenerational family reported.
Mendeliome v1.1944 CLDN2 Zornitza Stark edited their review of gene: CLDN2: Changed rating: RED
Mendeliome v1.1944 EMILIN1 Zornitza Stark Phenotypes for gene: EMILIN1 were changed from Neuronopathy, distal hereditary motor, type X, MIM# 620080; Aortic aneurysm, MONDO:0005160, EMILIN2-related to Neuronopathy, distal hereditary motor, type X, MIM# 620080; Arterial tortuosity-bone fragility syndrome, MIM# 620908
Mendeliome v1.1943 ACOX2 Sangavi Sivagnanasundram reviewed gene: ACOX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27647924, 27884763, 35395098; Phenotypes: congenital bile acid synthesis defect 6 MONDO:0015015; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1943 PRPF4 Sangavi Sivagnanasundram reviewed gene: PRPF4: Rating: GREEN; Mode of pathogenicity: None; Publications: 24419317; Phenotypes: inherited retinal dystrophy MONDO:0019118; Mode of inheritance: None
Mendeliome v1.1943 FZD6 Zornitza Stark Phenotypes for gene: FZD6 were changed from Nail disorder, nonsyndromic congenital, 1, MIM# 161050 to Nail disorder, nonsyndromic congenital, 1, MIM# 161050; Hydrops fetalis, MONDO:0015193, FZD6-related
Mendeliome v1.1942 FZD6 Zornitza Stark Publications for gene: FZD6 were set to 21665003; 23374899
Mendeliome v1.1941 FZD6 Zornitza Stark changed review comment from: PMIDs 33082562; 26036949; 28425981. Three FZD6 variants have been associated with two unrelated cases of fetal hyrdrops.; to: PMIDs 33082562; 26036949; 28425981. Three FZD6 variants have been associated with two unrelated cases of fetal hyrdrops. AMBER for this indication.
Mendeliome v1.1941 FZD6 Zornitza Stark edited their review of gene: FZD6: Changed phenotypes: Nail disorder, nonsyndromic congenital, 1, MIM# 161050, Hydrops fetalis, MONDO:0015193, FZD6-related
Mendeliome v1.1941 FZD6 Zornitza Stark edited their review of gene: FZD6: Added comment: PMIDs 33082562; 26036949; 28425981. Three FZD6 variants have been associated with two unrelated cases of fetal hyrdrops.; Changed publications: 21665003, 23374899, 33082562, 26036949, 28425981
Mendeliome v1.1941 TBC1D7 Zornitza Stark Publications for gene: TBC1D7 were set to 24515783; 23687350
Mendeliome v1.1940 TBC1D7 Zornitza Stark Classified gene: TBC1D7 as Green List (high evidence)
Mendeliome v1.1940 TBC1D7 Zornitza Stark Gene: tbc1d7 has been classified as Green List (High Evidence).
Mendeliome v1.1939 TBC1D7 Zornitza Stark edited their review of gene: TBC1D7: Changed rating: GREEN
Mendeliome v1.1939 TBC1D7 Zornitza Stark edited their review of gene: TBC1D7: Added comment: PMID: 36669495 reports additional individuals with compound het variants identified via trio RNASeq.; Changed publications: 24515783, 23687350, 36669495
Mendeliome v1.1939 GLIS2 Zornitza Stark Classified gene: GLIS2 as Green List (high evidence)
Mendeliome v1.1939 GLIS2 Zornitza Stark Gene: glis2 has been classified as Green List (High Evidence).
Mendeliome v1.1938 GLIS2 Zornitza Stark changed review comment from: Two families reported.; to: Three families (5 individuals) reported. Functional data.
Mendeliome v1.1938 GLIS2 Zornitza Stark edited their review of gene: GLIS2: Changed rating: GREEN
Mendeliome v1.1938 C17orf53 Zornitza Stark Phenotypes for gene: C17orf53 were changed from Primary ovarian insufficiency to Ovarian dysgenesis 11, MIM# 620897
Mendeliome v1.1937 C17orf53 Zornitza Stark Classified gene: C17orf53 as Green List (high evidence)
Mendeliome v1.1937 C17orf53 Zornitza Stark Gene: c17orf53 has been classified as Green List (High Evidence).
Mendeliome v1.1936 C17orf53 Zornitza Stark edited their review of gene: C17orf53: Added comment: PMID 38105698: Additional family reported with two sibs and compound het LoF variants.

HGNC approved name is HROB.; Changed rating: GREEN; Changed publications: 34707299, 31467087, 38105698; Changed phenotypes: Ovarian dysgenesis 11, MIM# 620897
Mendeliome v1.1936 CD274 Zornitza Stark Marked gene: CD274 as ready
Mendeliome v1.1936 CD274 Zornitza Stark Gene: cd274 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1936 CD274 Zornitza Stark Classified gene: CD274 as Amber List (moderate evidence)
Mendeliome v1.1936 CD274 Zornitza Stark Gene: cd274 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1935 RINT1 Zornitza Stark Phenotypes for gene: RINT1 were changed from Infantile liver failure syndrome 3, MIM# 618641 to Infantile liver failure syndrome 3, MIM# 618641; Hereditary spastic paraplegia, MONDO:0019064, RINT1-related
Mendeliome v1.1934 RINT1 Zornitza Stark Publications for gene: RINT1 were set to PMID: 31204009
Mendeliome v1.1933 RINT1 Zornitza Stark reviewed gene: RINT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37463447, 38990652; Phenotypes: Hereditary spastic paraplegia, MONDO:0019064, RINT1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1933 HDAC3 Zornitza Stark Marked gene: HDAC3 as ready
Mendeliome v1.1933 HDAC3 Zornitza Stark Gene: hdac3 has been classified as Green List (High Evidence).
Mendeliome v1.1933 HDAC3 Zornitza Stark Classified gene: HDAC3 as Green List (high evidence)
Mendeliome v1.1933 HDAC3 Zornitza Stark Gene: hdac3 has been classified as Green List (High Evidence).
Mendeliome v1.1932 HDAC3 Zornitza Stark gene: HDAC3 was added
gene: HDAC3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HDAC3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HDAC3 were set to 39047730
Phenotypes for gene: HDAC3 were set to Neurodevelopmental disorder, MONDO:0700092, HDAC3-related
Review for gene: HDAC3 was set to GREEN
Added comment: Six individuals with de novo missense variants in this gene and variable NDD phenotypes, including ID, seizures. Supportive functional data.
Sources: Literature
Mendeliome v1.1931 ITPR3 Zornitza Stark Phenotypes for gene: ITPR3 were changed from Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111 to Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111; Combined immunodeficiency, MONDO:0015131, ITPR3-related
Mendeliome v1.1930 ITPR3 Zornitza Stark Publications for gene: ITPR3 were set to 32949214; 24627108
Mendeliome v1.1929 ITPR3 Zornitza Stark Mode of inheritance for gene: ITPR3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1928 ITPR3 Zornitza Stark edited their review of gene: ITPR3: Changed publications: 32949214, 24627108, 36302985; Changed phenotypes: Charcot-Marie-Tooth disease, demyelinating, type 1J, MIM# 620111, Combined immunodeficiency, MONDO:0015131, ITPR3-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1928 UNC93B1 Zornitza Stark Phenotypes for gene: UNC93B1 were changed from Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 1 to Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 1, MIM#610551; Autoinflammatory syndrome, MONDO:0019751, UNC93B1-related
Mendeliome v1.1927 UNC93B1 Zornitza Stark Publications for gene: UNC93B1 were set to 16973841; 29768176
Mendeliome v1.1926 UNC93B1 Zornitza Stark Mode of inheritance for gene: UNC93B1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1925 UNC93B1 Zornitza Stark Classified gene: UNC93B1 as Green List (high evidence)
Mendeliome v1.1925 UNC93B1 Zornitza Stark Gene: unc93b1 has been classified as Green List (High Evidence).
Mendeliome v1.1924 UNC93B1 Zornitza Stark edited their review of gene: UNC93B1: Changed phenotypes: Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 1, MIM#610551, Autoinflammatory syndrome, MONDO:0019751, UNC93B1-related
Mendeliome v1.1924 UNC93B1 Zornitza Stark edited their review of gene: UNC93B1: Added comment: PMID 38869500: Rare missense substitutions in UNC93B1 in probands from five unrelated kindreds presenting with early onset SLE (two probands) or CBL (three probands). Clinical, genetic, and functional in vitro and ex vivo data demonstrating changes in TLR7/8 signalling and trafficking.; Changed rating: GREEN; Changed publications: 29768176, 38869500; Changed phenotypes: Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 1, Autoinflammatory syndrome, MONDO:0019751, UNC93B1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1924 CD274 Zornitza Stark gene: CD274 was added
gene: CD274 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CD274 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD274 were set to 38634869
Phenotypes for gene: CD274 were set to Immune dysregulation, autoimmunity and auto inflammation, MONDO:0957790
Review for gene: CD274 was set to AMBER
Added comment: Two siblings, born to second-degree consanguineous parents of Moroccan descent, both developed neonatal-onset T1D (diagnosed at the ages of 1 day and 7 wk, respectively). One sibling was subsequently diagnosed with asthma at the age of 5 mo, auto-immune hypothyroidism at the age of 3 years, and growth hormone (GH) deficiency at the age of 10 years. He also had mild intellectual disability with delayed language development. By contrast, his sister had no clinical manifestations other than T1D.

Homozygous for splicing variant. This is the ligand of PD1, deficiency of which is also linked to immune dysregulation. Functional data.
Sources: Literature
Mendeliome v1.1923 OAS2 Zornitza Stark Marked gene: OAS2 as ready
Mendeliome v1.1923 OAS2 Zornitza Stark Gene: oas2 has been classified as Green List (High Evidence).
Mendeliome v1.1923 OAS2 Zornitza Stark Classified gene: OAS2 as Green List (high evidence)
Mendeliome v1.1923 OAS2 Zornitza Stark Gene: oas2 has been classified as Green List (High Evidence).
Mendeliome v1.1922 OAS2 Zornitza Stark gene: OAS2 was added
gene: OAS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OAS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OAS2 were set to 36538032
Phenotypes for gene: OAS2 were set to Multisystem inflammatory syndrome, MONDO:0035375, OAS2-related
Review for gene: OAS2 was set to GREEN
Added comment: 3x unrelated patients with MIS-C after COVID infection. Patients displayed excessive inflammatory responses to intracellular dsRNA, SARS-CoV-2, SARS-CoV-2–infected cells, and their RNA, providing a plausible mechanism for MIS-C. Similar presentation to OAS1 and RNASEL. Functional data.
Sources: Literature
Mendeliome v1.1921 NFATC2 Zornitza Stark Phenotypes for gene: NFATC2 were changed from Skeletal system disorder MONDO:0005172 to Skeletal system disorder MONDO:0005172; Lymphoproliferative syndrome, MONDO:0016537, NFATC2-related
Mendeliome v1.1920 NFATC2 Zornitza Stark Publications for gene: NFATC2 were set to 35789258
Mendeliome v1.1919 NFATC2 Zornitza Stark reviewed gene: NFATC2: Rating: RED; Mode of pathogenicity: None; Publications: 38427060; Phenotypes: Lymphoproliferative syndrome, MONDO:0016537, NFATC2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1919 IKBKE Zornitza Stark Marked gene: IKBKE as ready
Mendeliome v1.1919 IKBKE Zornitza Stark Gene: ikbke has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1919 IKBKE Zornitza Stark Classified gene: IKBKE as Amber List (moderate evidence)
Mendeliome v1.1919 IKBKE Zornitza Stark Gene: ikbke has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1918 IKBKE Zornitza Stark gene: IKBKE was added
gene: IKBKE was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IKBKE was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IKBKE were set to 37937644
Phenotypes for gene: IKBKE were set to Encephalitis, acute, infection-induced, susceptibility to, MONDO:0800174, IKBKE-related
Review for gene: IKBKE was set to AMBER
Added comment: Single patient with recurrent HSV meningitis with supportive functional data.
Sources: Literature
Mendeliome v1.1917 SYCP2L Zornitza Stark Publications for gene: SYCP2L were set to 32303603
Mendeliome v1.1916 SYCP2L Zornitza Stark Classified gene: SYCP2L as Green List (high evidence)
Mendeliome v1.1916 SYCP2L Zornitza Stark Gene: sycp2l has been classified as Green List (High Evidence).
Mendeliome v1.1915 SYCP2L Zornitza Stark changed review comment from: PMID: 38521400 - A homozygous nonsense variant segregated with POI in a pedigree with two affected sisters (c.1528C>T, p.(Gln510Ter)) PMID: 32303603 - Two unrelated individuals with premature ovarian insufficiency and homozygous variants (c.150_151del (p.Ser52Profs*7), c.999A>G (p.Ile333Met)) in SYCP2L. Concordant mouse model.; to: PMID: 38521400 - A homozygous nonsense variant segregated with POI in a pedigree with two affected sisters c.1528C>T, p.(Gln510Ter)
Mendeliome v1.1915 SYCP2L Zornitza Stark reviewed gene: SYCP2L: Rating: GREEN; Mode of pathogenicity: None; Publications: 38521400; Phenotypes: Premature ovarian failure 24, MIM# 620840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1915 CD28 Zornitza Stark Phenotypes for gene: CD28 were changed from Hereditary predisposition to infections, MONDO:0015979, CD28-related; isolated susceptibility to cutaneous α- and γ-HPVs to Immunodeficiency-123 with HPV-related verrucosis (IMD123), MIM#620901; isolated susceptibility to cutaneous α- and γ-HPVs
Mendeliome v1.1914 CD28 Zornitza Stark edited their review of gene: CD28: Changed phenotypes: Immunodeficiency-123 with HPV-related verrucosis (IMD123), MIM#620901, isolated susceptibility to cutaneous α- and γ-HPVs
Mendeliome v1.1914 CD28 Zornitza Stark edited their review of gene: CD28: Changed phenotypes: Immunodeficiency-123 with HPV-related verrucosis (IMD123), MIM#62090, isolated susceptibility to cutaneous α- and γ-HPVs
Mendeliome v1.1914 NEK8 Zornitza Stark Phenotypes for gene: NEK8 were changed from Renal-hepatic-pancreatic dysplasia 2, MIM# 615415; MONDO:0014174; Familial renal cystic disease MONDO:0019741, NEK8-related, dominant to Renal-hepatic-pancreatic dysplasia 2, MIM# 615415; MONDO:0014174; Polycystic kidney disease 8, MIM# 620903
Mendeliome v1.1913 NEK8 Zornitza Stark edited their review of gene: NEK8: Changed phenotypes: Renal-hepatic-pancreatic dysplasia 2, MIM# 615415, MONDO:0014174, Polycystic kidney disease 8, MIM# 620903
Mendeliome v1.1913 LEO1 Ain Roesley changed review comment from: cohort of individuals with delayed motor and speech development, ASD

8x de novo – 6x missense + 2x PTC
1x pat splice (father unaffected)
2x unknown_inh PTCs

Of the missense variants, G370E has 8 hets in gnomad v4

This gene is not constraint for LoF with 4 hets with an NMD variant in gnomad v4
Sources: Literature; to: cohort of individuals with delayed motor and speech development, ASD

8x de novo – 6x missense + 2x PTC
1x pat splice (father unaffected)
2x unknown_inh PTCs

Of the missense variants, G370E has 8 hets in gnomad v4

This gene is not constraint for LoF with 4 hets with an NMD variant in gnomad v4
3 of the missense are said to lie within a region of missense constraint, however this isn't the case in v4

Sources: Literature
Mendeliome v1.1913 PCBP2 Ain Roesley Marked gene: PCBP2 as ready
Mendeliome v1.1913 PCBP2 Ain Roesley Gene: pcbp2 has been classified as Green List (High Evidence).
Mendeliome v1.1913 PCBP2 Ain Roesley Classified gene: PCBP2 as Green List (high evidence)
Mendeliome v1.1913 PCBP2 Ain Roesley Gene: pcbp2 has been classified as Green List (High Evidence).
Mendeliome v1.1912 PCBP2 Ain Roesley gene: PCBP2 was added
gene: PCBP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PCBP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PCBP2 were set to 38965372
Phenotypes for gene: PCBP2 were set to neurodevelopmental disorder MONDO:0700092, PCBP2-related
Review for gene: PCBP2 was set to GREEN
gene: PCBP2 was marked as current diagnostic
Added comment: 3x individuals with de novo variants
Motor and speech delay and ASD
2x missense + 1x fs

There are 2 NMD variants with 9 and 8 hets respectively in gnomad v4, however the IGV looks to be low quality
Sources: Literature
Mendeliome v1.1911 LEO1 Ain Roesley changed review comment from: enrichment of a neurodev cohort
LEO1:
8x de novo – 6x missense + 2x PTC
1x pat splice (father unaffected)
2x unknown_inh PTCs

Of the missense variants, G370E has 8 hets in gnomad v4

This gene is not constraint for LoF with 4 hets with an NMD variant in gnomad v4
Sources: Literature; to: cohort of individuals with delayed motor and speech development, ASD

8x de novo – 6x missense + 2x PTC
1x pat splice (father unaffected)
2x unknown_inh PTCs

Of the missense variants, G370E has 8 hets in gnomad v4

This gene is not constraint for LoF with 4 hets with an NMD variant in gnomad v4
Sources: Literature
Mendeliome v1.1911 LEO1 Ain Roesley changed review comment from: enrichment of a neurodev cohort
LEO1:
8x de novo – 6x missense + 2x PTC
1x pat splice
2x unknown_inh PTCs

Of the missense variants, G370E has 8 hets in gnomad v4

This gene is not constraint for LoF with 4 hets with an NMD variant in gnomad v4
Sources: Literature; to: enrichment of a neurodev cohort
LEO1:
8x de novo – 6x missense + 2x PTC
1x pat splice (father unaffected)
2x unknown_inh PTCs

Of the missense variants, G370E has 8 hets in gnomad v4

This gene is not constraint for LoF with 4 hets with an NMD variant in gnomad v4
Sources: Literature
Mendeliome v1.1911 LEO1 Ain Roesley Marked gene: LEO1 as ready
Mendeliome v1.1911 LEO1 Ain Roesley Gene: leo1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1911 LEO1 Ain Roesley Classified gene: LEO1 as Amber List (moderate evidence)
Mendeliome v1.1911 LEO1 Ain Roesley Gene: leo1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1910 LEO1 Ain Roesley gene: LEO1 was added
gene: LEO1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LEO1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LEO1 were set to 38965372
Phenotypes for gene: LEO1 were set to neurodevelopmental disorder MONDO:0700092, LEO-1 related
Review for gene: LEO1 was set to AMBER
gene: LEO1 was marked as current diagnostic
Added comment: enrichment of a neurodev cohort
LEO1:
8x de novo – 6x missense + 2x PTC
1x pat splice
2x unknown_inh PTCs

Of the missense variants, G370E has 8 hets in gnomad v4

This gene is not constraint for LoF with 4 hets with an NMD variant in gnomad v4
Sources: Literature
Mendeliome v1.1909 KCNJ10 Zornitza Stark Phenotypes for gene: KCNJ10 were changed from SESAME syndrome, MIM# 612780 to SESAME syndrome, MIM# 612780; Paroxysmal dyskinesia, MONDO:0015427, KCNJ10-related
Mendeliome v1.1908 KCNJ10 Zornitza Stark Publications for gene: KCNJ10 were set to 19289823; 19420365; 21849804; 11466414
Mendeliome v1.1907 KCNJ10 Zornitza Stark Mode of inheritance for gene: KCNJ10 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1906 KCNJ10 Zornitza Stark edited their review of gene: KCNJ10: Added comment: PMID 38979912: 11 individuals from 8 unrelated families reported with variants in this gene and paroxysmal dyskinesia. Notably one was the parent of a child with recessive SeSAME syndrome (established gene-disease association). Patch-clamp recordings in HEK293T cells revealed apparent reductions in K+ currents of the patient-derived variants, indicating a loss-of-function. In Drosophila, milder hyperexcitability phenotypes were observed in heterozygous Irk2 knock-in flies compared to homozygotes, supporting haploinsufficiency as the mechanism for the detected heterozygous variants. Electrophysiological recordings showed that excitatory neurons in Irk2 haploinsufficiency flies exhibited increased excitability, and glia-specific complementation with human Kir4.1 rescued the Irk2 mutant phenotypes.; Changed publications: 19289823, 19420365, 21849804, 11466414, 38979912; Changed phenotypes: SESAME syndrome, MIM# 612780, Paroxysmal dyskinesia, MONDO:0015427, KCNJ10-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1906 SLC45A1 Zornitza Stark Publications for gene: SLC45A1 were set to 28434495
Mendeliome v1.1905 SLC45A1 Zornitza Stark Classified gene: SLC45A1 as Green List (high evidence)
Mendeliome v1.1905 SLC45A1 Zornitza Stark Gene: slc45a1 has been classified as Green List (High Evidence).
Mendeliome v1.1904 SLC45A1 Zornitza Stark edited their review of gene: SLC45A1: Added comment: PMID 39003656: additional individual with compound het missense variants and supportive functional data.; Changed rating: GREEN; Changed publications: 28434495, 39003656
Mendeliome v1.1904 HBS1L Bryony Thompson Marked gene: HBS1L as ready
Mendeliome v1.1904 HBS1L Bryony Thompson Gene: hbs1l has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1904 HBS1L Bryony Thompson Classified gene: HBS1L as Amber List (moderate evidence)
Mendeliome v1.1904 HBS1L Bryony Thompson Gene: hbs1l has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1903 HBS1L Bryony Thompson gene: HBS1L was added
gene: HBS1L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HBS1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HBS1L were set to 38966981; 24288412; 30707697
Phenotypes for gene: HBS1L were set to Retinal disorder MONDO:0005283
Review for gene: HBS1L was set to AMBER
Added comment: A single case with biallelic variants reported with retinal dystrophy, poor growth and neurodevelopmental delay (originally reported in 2013). A hypomorph mouse model demonstrated defective development of photoreceptor cells.
Sources: Literature
Mendeliome v1.1902 SRPK3 Zornitza Stark Phenotypes for gene: SRPK3 were changed from Myopathy, MONDO:0005336, digenic SRPK3- and TTN-related to Myopathy, MONDO:0005336, digenic SRPK3- and TTN-related; Neurodevelopmental disorder, MONDO:0700092, SRPK3-related
Mendeliome v1.1901 SRPK3 Zornitza Stark Publications for gene: SRPK3 were set to 38429495
Mendeliome v1.1900 SRPK3 Zornitza Stark edited their review of gene: SRPK3: Changed phenotypes: Myopathy, MONDO:0005336, digenic SRPK3- and TTN-related, Neurodevelopmental disorder, MONDO:0700092, SRPK3-related
Mendeliome v1.1900 SRPK3 Zornitza Stark edited their review of gene: SRPK3: Added comment: PMID 39073169: 9 individuals from 5 unrelated families reported with 4 missense and 1 putative truncating variant and a neurodevelopmental phenotype. The 8 patients ascertained postnatally shared common clinical features including intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia. A ninth case, ascertained prenatally, had a complex structural brain phenotype. Supportive animal model data (mouse and zebrafish).; Changed publications: 38429495, 39073169
Mendeliome v1.1900 RBBP5 Ain Roesley Marked gene: RBBP5 as ready
Mendeliome v1.1900 RBBP5 Ain Roesley Gene: rbbp5 has been classified as Green List (High Evidence).
Mendeliome v1.1900 NDC1 Bryony Thompson Marked gene: NDC1 as ready
Mendeliome v1.1900 NDC1 Bryony Thompson Gene: ndc1 has been classified as Green List (High Evidence).
Mendeliome v1.1900 RBBP5 Ain Roesley changed review comment from: 5x Indivis (4x de novo) = 3x PTCs + 2x missense

4/5 dev delay/ID
2/5 short stature (<=-3 SD) + 2/5 <= -2 SD
1/5 microcephaly (< -3 SD) + 3/5 <= -2 SD
2/5 SNHL
2/5 seizures
3/5 hypotonia; to: 5x Indivs (4x de novo) = 3x PTCs + 2x missense

4/5 dev delay/ID
2/5 short stature (<=-3 SD) + 2/5 <= -2 SD
1/5 microcephaly (< -3 SD) + 3/5 <= -2 SD
2/5 SNHL
2/5 seizures
3/5 hypotonia
Mendeliome v1.1900 NDC1 Bryony Thompson Classified gene: NDC1 as Green List (high evidence)
Mendeliome v1.1900 NDC1 Bryony Thompson Gene: ndc1 has been classified as Green List (High Evidence).
Mendeliome v1.1899 NDC1 Bryony Thompson gene: NDC1 was added
gene: NDC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NDC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDC1 were set to 39003500; 19782045
Phenotypes for gene: NDC1 were set to triple-A syndrome MONDO:0009279
Review for gene: NDC1 was set to GREEN
Added comment: 7 cases from 4 consanguineous families (3 different variants: 1 intronic variants that causes in-frame RNA splice impact, 2 missense) with a Triple-A-like syndrome (including ID and neuropathy). Supporting cellular localisation studies were conducted in patient cell lines with the splice variant. NDC1 is required to anchor ALADIN (encoded by AAAS, the gene that causes Triple-A syndrome) in the nuclear pore complex.
Sources: Literature
Mendeliome v1.1898 OPDM_ABCD3_GCC Bryony Thompson Marked STR: OPDM_ABCD3_GCC as ready
Mendeliome v1.1898 OPDM_ABCD3_GCC Bryony Thompson Str: opdm_abcd3_gcc has been classified as Green List (High Evidence).
Mendeliome v1.1898 OPDM_ABCD3_GCC Bryony Thompson Classified STR: OPDM_ABCD3_GCC as Green List (high evidence)
Mendeliome v1.1898 OPDM_ABCD3_GCC Bryony Thompson Str: opdm_abcd3_gcc has been classified as Green List (High Evidence).
Mendeliome v1.1897 OPDM_ABCD3_GCC Bryony Thompson STR: OPDM_ABCD3_GCC was added
STR: OPDM_ABCD3_GCC was added to Mendeliome. Sources: Literature
Mode of inheritance for STR: OPDM_ABCD3_GCC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: OPDM_ABCD3_GCC were set to 39068203
Phenotypes for STR: OPDM_ABCD3_GCC were set to Oculopharyngodistal myopathy MONDO:0025193
Review for STR: OPDM_ABCD3_GCC was set to GREEN
STR: OPDM_ABCD3_GCC was marked as clinically relevant
Added comment: 35 OPDM individuals from 8 unrelated families from Australia, the UK, and France with an ABCD3 5’UTR CGG repeat. Affected individuals had repeat expansions ranging from 118-694 (n=19). 7 repeats is the median repeat size in non-neurological controls from the GE 100,000 Genome Project. 10 controls had estimated repeats >50, up to ~93. 50 repeats would be a safe cut-off for normal
Sources: Literature
Mendeliome v1.1896 RBBP5 Ain Roesley Classified gene: RBBP5 as Green List (high evidence)
Mendeliome v1.1896 RBBP5 Ain Roesley Gene: rbbp5 has been classified as Green List (High Evidence).
Mendeliome v1.1895 RBBP5 Ain Roesley commented on gene: RBBP5: 5x Indivis (4x de novo) = 3x PTCs + 2x missense

4/5 dev delay/ID
2/5 short stature (<=-3 SD) + 2/5 <= -2 SD
1/5 microcephaly (< -3 SD) + 3/5 <= -2 SD
2/5 SNHL
2/5 seizures
3/5 hypotonia
Mendeliome v1.1895 RBBP5 Ain Roesley Deleted their comment
Mendeliome v1.1895 RBBP5 Ain Roesley gene: RBBP5 was added
gene: RBBP5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RBBP5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RBBP5 were set to 39036895
Phenotypes for gene: RBBP5 were set to neurodevelopmental disorder MONDO:0700092, RBBP5-related
Review for gene: RBBP5 was set to GREEN
gene: RBBP5 was marked as current diagnostic
Added comment: 5 individuals with de novo variants - 3x PTCs + 2x missense

2/5 short stature (> 3SD; 2x >=-2SD)
1/5 microcephaly (> 3SD; 3x >=-2SD)
4/5 dev delay/ID
2/5 SNHL
2/5 Seizures
3/5 hypotonia
Sources: Literature
Mendeliome v1.1894 BBS4 Andrew Coventry reviewed gene: BBS4: Rating: GREEN; Mode of pathogenicity: None; Publications: 11381270 12016587 10874630; Phenotypes: Bardet-Biedl syndrome 4 MIM#615982; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1894 LDB3 Bryony Thompson Deleted their comment
Mendeliome v1.1894 LDB3 Bryony Thompson Classified gene: LDB3 as Green List (high evidence)
Mendeliome v1.1894 LDB3 Bryony Thompson Added comment: Comment on list classification: Monoallelic DCM association is still Amber
Mendeliome v1.1894 LDB3 Bryony Thompson Gene: ldb3 has been classified as Green List (High Evidence).
Mendeliome v1.1893 LDB3 Bryony Thompson Added comment: Comment on mode of inheritance: AD missense variants in LDB3 that affect only short isoforms are associated with skeletal myopathies, while AR LoF variants cause paediatric cardiomyopathy
Mendeliome v1.1893 LDB3 Bryony Thompson Mode of inheritance for gene: LDB3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1892 LDB3 Bryony Thompson reviewed gene: LDB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 36253531, 32922198; Phenotypes: dilated cardiomyopathy MONDO:0005021; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1892 SNUPN Zornitza Stark Phenotypes for gene: SNUPN were changed from autosomal recessive limb-girdle muscular dystrophy MONDO:0015152 to Muscular dystrophy, limb-girdle, autosomal recessive 29, MIM# 620793
Mendeliome v1.1891 SNUPN Zornitza Stark reviewed gene: SNUPN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Muscular dystrophy, limb-girdle, autosomal recessive 29, MIM# 620793; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1891 SPATA5 Zornitza Stark commented on gene: SPATA5: DEFINITIVE by ClinGen.
Mendeliome v1.1891 SPATA5 Zornitza Stark Marked gene: SPATA5 as ready
Mendeliome v1.1891 SPATA5 Zornitza Stark Added comment: Comment when marking as ready: New gene name is AFG2A
Mendeliome v1.1891 SPATA5 Zornitza Stark Gene: spata5 has been classified as Green List (High Evidence).
Mendeliome v1.1891 SPATA5 Zornitza Stark Tag new gene name tag was added to gene: SPATA5.
Mendeliome v1.1891 CRNKL1 Zornitza Stark Marked gene: CRNKL1 as ready
Mendeliome v1.1891 CRNKL1 Zornitza Stark Gene: crnkl1 has been classified as Green List (High Evidence).
Mendeliome v1.1891 CRNKL1 Zornitza Stark Classified gene: CRNKL1 as Green List (high evidence)
Mendeliome v1.1891 CRNKL1 Zornitza Stark Gene: crnkl1 has been classified as Green List (High Evidence).
Mendeliome v1.1890 DCC Zornitza Stark Publications for gene: DCC were set to 20431009; 31697046; 21242494; 28250454; 28250456; 25763452
Mendeliome v1.1889 DCC Zornitza Stark commented on gene: DCC: Third family reported with biallelic variants and scoliosis, PMID 33141514; novel homozygous frameshift variant (p.Asn800Lysfs*11) in three individuals.
Mendeliome v1.1889 SLC7A5 Zornitza Stark Marked gene: SLC7A5 as ready
Mendeliome v1.1889 SLC7A5 Zornitza Stark Gene: slc7a5 has been classified as Red List (Low Evidence).
Mendeliome v1.1889 SLC7A5 Zornitza Stark Classified gene: SLC7A5 as Red List (low evidence)
Mendeliome v1.1889 SLC7A5 Zornitza Stark Gene: slc7a5 has been classified as Red List (Low Evidence).
Mendeliome v1.1888 SLC7A5 Sangavi Sivagnanasundram gene: SLC7A5 was added
gene: SLC7A5 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: SLC7A5 was set to Unknown
Publications for gene: SLC7A5 were set to 29884839
Phenotypes for gene: SLC7A5 were set to Large neutral amino acid transporter deficiency (MIM#600182)
Review for gene: SLC7A5 was set to RED
Added comment: Classified an inborn error of amino acid metabolism by IEMbase however more evidence is required to support the gene-disease association.
Sources: Other
Mendeliome v1.1888 CRNKL1 Mark Cleghorn gene: CRNKL1 was added
gene: CRNKL1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: CRNKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CRNKL1 were set to complex neurodevelopmental disorder MONDO:0100038
Review for gene: CRNKL1 was set to GREEN
Added comment: Unpublished, presented at ESHG June 2024 - Louise Bicknell, University of Otago NZ
8 unrelated families via gene matcher with rare, de novo, missense variants in CRNKL1
severe microcephaly (all, -8 to -11 SD)
ID/epilepsy
pontocerebellar hypoplasia (6/8)
simplified gyration (8/8)
7 variants are missense at p.Arg267 residue
1 variant missense at p.Arg301
RNA-seq on patient fibroblasts - no alteration in gene expression
Zebrafish homolog of Arg267 and Arg301 - mimics observed phenotype (reduced brain development), increased in embryo apoptosis
RNA seq on affected zebrafish embryos - transcriptome strongly disrupted
Splicing analysis in progress

CRKNL1 supports U6 structure in spliceosome
Sources: Other
Mendeliome v1.1888 ZNF483 Zornitza Stark Marked gene: ZNF483 as ready
Mendeliome v1.1888 ZNF483 Zornitza Stark Gene: znf483 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1888 ZNF483 Zornitza Stark Mode of inheritance for gene: ZNF483 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1887 ZNF483 Zornitza Stark Classified gene: ZNF483 as Amber List (moderate evidence)
Mendeliome v1.1887 ZNF483 Zornitza Stark Gene: znf483 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1886 ZNF483 Mark Cleghorn gene: ZNF483 was added
gene: ZNF483 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF483 was set to Unknown
Publications for gene: ZNF483 were set to 38951643
Phenotypes for gene: ZNF483 were set to primary ovarian failure MONDO:0005387
Review for gene: ZNF483 was set to AMBER
Added comment: PMID: 38951643, ESHG 2024 presentation
Large cohort assessing PRS for age of menarche
Noted rare PTVs in ZNF483 assoc w earlier menarche
No individual case information in this study
Sources: Literature
Mendeliome v1.1886 DDOST Achchuthan Shanmugasundram reviewed gene: DDOST: Rating: GREEN; Mode of pathogenicity: None; Publications: 34462534; Phenotypes: Congenital disorder of glycosylation, type Ir, OMIM:614507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1886 SENP7 Zornitza Stark Publications for gene: SENP7 were set to PMID: 37460201
Mendeliome v1.1885 SENP7 Zornitza Stark Classified gene: SENP7 as Green List (high evidence)
Mendeliome v1.1885 SENP7 Zornitza Stark Gene: senp7 has been classified as Green List (High Evidence).
Mendeliome v1.1884 SENP7 Zornitza Stark reviewed gene: SENP7: Rating: GREEN; Mode of pathogenicity: None; Publications: 38972567, 37460201; Phenotypes: Arthrogryposis multiplex congenita, MONDO:0015168, SENP7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1884 MYZAP Zornitza Stark changed review comment from: 10 individuals from four unrelated families with bi-allelic variants in this gene with DCM. Supportive zebrafish model. Note the MYZAP and GCOM1 genes are part of the GRINL1A complex transcription unit. Some of the reported variants affect GCOM1 with postulated effect on MYZAP due to read through transcription (two families), and in the rest of the families MYZAP was affected directly.
Sources: Literature; to: 10 individuals from four unrelated families with bi-allelic variants in this gene with DCM. Supportive zebrafish model.

The MYZAP gene is part of the GRINL1A complex transcription unit (CTU), or GCOM1, which also includes the downstream POLR2M gene, or GRINL1A.. Some of the reported variants affect GCOM1 with postulated effect on MYZAP due to read through transcription (two families), and in the rest of the families MYZAP was affected directly.

Transcription from an upstream promoter within the GRINL1A CTU produces 2 types of alternatively spliced transcripts: MYZAP transcripts, also called GRINL1A upstream (GUP) transcripts, which include only exons from the MYZAP gene, and GRINL1A combined (GCOM) transcripts, which include exons from both the MYZAP gene and the downstream POLR2M gene. Transcription of the POLR2M gene initiates at a downstream promoter within the GRINL1A CTU and produces alternatively spliced POLR2M transcripts, also called GRINL1A downstream (GDOWN) transcripts, which include only exons from the POLR2M gene
Sources: Literature
Mendeliome v1.1884 MYZAP Zornitza Stark Marked gene: MYZAP as ready
Mendeliome v1.1884 MYZAP Zornitza Stark Gene: myzap has been classified as Green List (High Evidence).
Mendeliome v1.1884 MYZAP Zornitza Stark Classified gene: MYZAP as Green List (high evidence)
Mendeliome v1.1884 MYZAP Zornitza Stark Gene: myzap has been classified as Green List (High Evidence).
Mendeliome v1.1883 MYZAP Zornitza Stark gene: MYZAP was added
gene: MYZAP was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MYZAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYZAP were set to 34899865; 35840178; 38436102; 20093627
Phenotypes for gene: MYZAP were set to Cardiomyopathy, dilated, 2K, MIM# 620894
Review for gene: MYZAP was set to GREEN
Added comment: 10 individuals from four unrelated families with bi-allelic variants in this gene with DCM. Supportive zebrafish model. Note the MYZAP and GCOM1 genes are part of the GRINL1A complex transcription unit. Some of the reported variants affect GCOM1 with postulated effect on MYZAP due to read through transcription (two families), and in the rest of the families MYZAP was affected directly.
Sources: Literature
Mendeliome v1.1882 PRODH2 Zornitza Stark Marked gene: PRODH2 as ready
Mendeliome v1.1882 PRODH2 Zornitza Stark Gene: prodh2 has been classified as Red List (Low Evidence).
Mendeliome v1.1882 PRODH2 Zornitza Stark Classified gene: PRODH2 as Red List (low evidence)
Mendeliome v1.1882 PRODH2 Zornitza Stark Gene: prodh2 has been classified as Red List (Low Evidence).
Mendeliome v1.1881 SELENBP1 Zornitza Stark Marked gene: SELENBP1 as ready
Mendeliome v1.1881 SELENBP1 Zornitza Stark Gene: selenbp1 has been classified as Green List (High Evidence).
Mendeliome v1.1881 SELENBP1 Zornitza Stark Classified gene: SELENBP1 as Green List (high evidence)
Mendeliome v1.1881 SELENBP1 Zornitza Stark Gene: selenbp1 has been classified as Green List (High Evidence).
Mendeliome v1.1880 RNU4-2 Zornitza Stark Publications for gene: RNU4-2 were set to 38645094
Mendeliome v1.1879 RNU4-2 Zornitza Stark edited their review of gene: RNU4-2: Changed publications: 38991538
Mendeliome v1.1879 FDXR Zornitza Stark Phenotypes for gene: FDXR were changed from Auditory neuropathy and optic atrophy, MIM#617717 to Auditory neuropathy and optic atrophy, MIM#617717; Neurodevelopmental disorder with mitochondrial abnormalities, optic atrophy, and developmental regression, MIM# 620887
Mendeliome v1.1878 FDXR Zornitza Stark Publications for gene: FDXR were set to 30250212; 28965846
Mendeliome v1.1877 FDXR Zornitza Stark edited their review of gene: FDXR: Added comment: Multiple reports of individuals with extra-ocular features, including ID and regression.; Changed publications: 30250212, 28965846, 29040572, 33348459, 37046037, 37481223; Changed phenotypes: Auditory neuropathy and optic atrophy, MIM#617717, Neurodevelopmental disorder with mitochondrial abnormalities, optic atrophy, and developmental regression, MIM# 620887
Mendeliome v1.1877 RNU4-2 Zornitza Stark Phenotypes for gene: RNU4-2 were changed from Neurodevelopmental disorder, MONDO:0700092, RNU4-2 related to Neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language, MIM# 620851
Mendeliome v1.1876 RNU4-2 Zornitza Stark edited their review of gene: RNU4-2: Changed phenotypes: Neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language, MIM# 620851
Mendeliome v1.1876 SELENBP1 Sangavi Sivagnanasundram gene: SELENBP1 was added
gene: SELENBP1 was added to Mendeliome. Sources: ClinGen
Mode of inheritance for gene: SELENBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SELENBP1 were set to 29255262
Phenotypes for gene: SELENBP1 were set to extraoral halitosis due to methanethiol oxidase deficiency MONDO:0029144
Review for gene: SELENBP1 was set to GREEN
Added comment: 3 unrelated probands in one publication. All reported individuals had a “cabbage-like” breath odour due to the elevated levels of methanethiol and dimethylsulfide in their breath.
Knockout mouse model recapitulating the human phenotype including the biochemical characteristics.

Classified as Moderate by ClinGen Aminoacidopathy GCEP on 11/11/2022
https://search.clinicalgenome.org/CCID:006103
Sources: ClinGen
Mendeliome v1.1876 PRODH2 Sangavi Sivagnanasundram gene: PRODH2 was added
gene: PRODH2 was added to Mendeliome. Sources: ClinGen
Mode of inheritance for gene: PRODH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRODH2 were set to 27139199
Phenotypes for gene: PRODH2 were set to hydroxyprolinemia MONDO:0009374
Review for gene: PRODH2 was set to RED
Added comment: PMID: 27139199
Variants reported in 6 individuals however only 2 cases presented with intermittant biochemical phenotype however the cause remains unclear. The rest of the individuals were asymptomatic suggesting that hydroxyprolinemia is a benign condition.

Classified as Limited by ClinGen Aminoacidopathy GCEP on 12/12/2022
https://search.clinicalgenome.org/CCID:005893
Sources: ClinGen
Mendeliome v1.1876 GAS2 Zornitza Stark Marked gene: GAS2 as ready
Mendeliome v1.1876 GAS2 Zornitza Stark Gene: gas2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1876 GAS2 Zornitza Stark Classified gene: GAS2 as Amber List (moderate evidence)
Mendeliome v1.1876 GAS2 Zornitza Stark Gene: gas2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1875 GAS2 Zornitza Stark gene: GAS2 was added
gene: GAS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GAS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GAS2 were set to 33964205
Phenotypes for gene: GAS2 were set to Deafness, autosomal recessive 125, MIM#620877
Review for gene: GAS2 was set to AMBER
Added comment: Single family reported with four affected brothers and a splicing variant. Supportive mouse model.
Sources: Literature
Mendeliome v1.1874 KIF1A Zornitza Stark Phenotypes for gene: KIF1A were changed from Neuropathy, hereditary sensory, type IIC, MIM# 614213; NESCAV syndrome, MIM# 614255; Spastic paraplegia 30, MIM# 610357 to Neuropathy, hereditary sensory, type IIC, MIM# 614213; NESCAV syndrome, MIM# 614255; Spastic paraplegia 30, autosomal dominant MIM# 610357; Spastic paraplegia 30, autosomal recessive 620607
Mendeliome v1.1873 KIF1A Zornitza Stark edited their review of gene: KIF1A: Changed phenotypes: Neuropathy, hereditary sensory, type IIC, MIM# 614213, NESCAV syndrome, MIM# 614255, Spastic paraplegia 30, autosomal dominant MIM# 610357, Spastic paraplegia 30, autosomal recessive 620607
Mendeliome v1.1873 SREBF2 Zornitza Stark Marked gene: SREBF2 as ready
Mendeliome v1.1873 SREBF2 Zornitza Stark Gene: srebf2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1873 SREBF2 Zornitza Stark Classified gene: SREBF2 as Amber List (moderate evidence)
Mendeliome v1.1873 SREBF2 Zornitza Stark Gene: srebf2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1872 SREBF2 Zornitza Stark gene: SREBF2 was added
gene: SREBF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SREBF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SREBF2 were set to 38847193
Phenotypes for gene: SREBF2 were set to Neurocutaneous syndrome, MONDO:0042983, SREBF2-related
Review for gene: SREBF2 was set to AMBER
Added comment: Two individuals with de novo missense variants, presenting with neurological, cutaneous and skeletal features; supportive functional data.
Sources: Literature
Mendeliome v1.1871 USP25 Zornitza Stark Marked gene: USP25 as ready
Mendeliome v1.1871 USP25 Zornitza Stark Gene: usp25 has been classified as Green List (High Evidence).
Mendeliome v1.1871 USP25 Zornitza Stark Classified gene: USP25 as Green List (high evidence)
Mendeliome v1.1871 USP25 Zornitza Stark Gene: usp25 has been classified as Green List (High Evidence).
Mendeliome v1.1870 C10orf71 Zornitza Stark Marked gene: C10orf71 as ready
Mendeliome v1.1870 C10orf71 Zornitza Stark Gene: c10orf71 has been classified as Green List (High Evidence).
Mendeliome v1.1870 C10orf71 Zornitza Stark Classified gene: C10orf71 as Green List (high evidence)
Mendeliome v1.1870 C10orf71 Zornitza Stark Gene: c10orf71 has been classified as Green List (High Evidence).
Mendeliome v1.1869 PSMC5 Zornitza Stark Phenotypes for gene: PSMC5 were changed from Developmental disorders to Neurodevelopmental disorder (MONDO#0700092), PSMC5-related
Mendeliome v1.1868 PSMC5 Zornitza Stark Publications for gene: PSMC5 were set to 33057194
Mendeliome v1.1867 PSMC5 Zornitza Stark Classified gene: PSMC5 as Green List (high evidence)
Mendeliome v1.1867 PSMC5 Zornitza Stark Gene: psmc5 has been classified as Green List (High Evidence).
Mendeliome v1.1866 PSMF1 Zornitza Stark Marked gene: PSMF1 as ready
Mendeliome v1.1866 PSMF1 Zornitza Stark Gene: psmf1 has been classified as Green List (High Evidence).
Mendeliome v1.1866 PSMF1 Zornitza Stark Classified gene: PSMF1 as Green List (high evidence)
Mendeliome v1.1866 PSMF1 Zornitza Stark Gene: psmf1 has been classified as Green List (High Evidence).
Mendeliome v1.1865 PSMF1 Zornitza Stark gene: PSMF1 was added
gene: PSMF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMF1 were set to https://www.medrxiv.org/content/10.1101/2024.06.19.24308302v1
Phenotypes for gene: PSMF1 were set to Complex neurodevelopmental disorder with motor features, MONDO:0100516, PSMF1-related
Review for gene: PSMF1 was set to GREEN
Added comment: 22 individuals from 15 families reported with a range of neurological phenotypes ranging from early-onset Parkinson's disease; childhood conditions typified by ID and a range of movement disorders; through to perinatal lethal presentations with arthrogryposis multiplex. Genotype-phenotype correlation: biallelic missense variants resulted in the milder phenotypes, while bi-allelic LoF variants in the more severe phenotypes. Supportive functional data.
Sources: Literature
Mendeliome v1.1864 POLD3 Zornitza Stark Phenotypes for gene: POLD3 were changed from Severe combined immunodeficiency MONDO:0015974 to Immunodeficiency 122, MIM# 620869
Mendeliome v1.1863 POLD3 Zornitza Stark Publications for gene: POLD3 were set to 37030525; 36395985; 27524497
Mendeliome v1.1862 POLD3 Zornitza Stark Classified gene: POLD3 as Green List (high evidence)
Mendeliome v1.1862 POLD3 Zornitza Stark Gene: pold3 has been classified as Green List (High Evidence).
Mendeliome v1.1861 POLD3 Zornitza Stark reviewed gene: POLD3: Rating: GREEN; Mode of pathogenicity: None; Publications: 38099988; Phenotypes: Immunodeficiency 122, MIM# 620869; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1861 TUBA4A Bryony Thompson Classified gene: TUBA4A as Green List (high evidence)
Mendeliome v1.1861 TUBA4A Bryony Thompson Gene: tuba4a has been classified as Green List (High Evidence).
Mendeliome v1.1860 TUBA4A Bryony Thompson reviewed gene: TUBA4A: Rating: GREEN; Mode of pathogenicity: None; Publications: 38884572, 37418012; Phenotypes: Hereditary ataxia MONDO:0100309, TUBA4A-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1860 PSMC5 Rylee Peters reviewed gene: PSMC5: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38776958, 38293138; Phenotypes: Neurodevelopmental disorder (MONDO#0700092), PSMC5-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1860 VPS50 Ain Roesley changed review comment from: 1x proband Chet for a nonsense p.(Lys5*) and a complex structural variant of a 4.3Mb inversion, flanked by 170kb and 428kb deletions, respectively. The 428kb deletion spans the entire VPS50 gene.

Sanger confirmed the Lys5* to be 'homozygous' in the proband.

Phenotypes include:
microcephaly, nystagmus, seizures, hypoplastic corpus callous, neonatal low GGT cholesatsis, hepatomegaly, failure to thrive; to: 1x proband Chet for a nonsense p.(Lys5*) and a complex structural variant of a 4.3Mb inversion, flanked by 170kb and 428kb deletions, respectively. The 428kb deletion spans the entire VPS50 gene.

Sanger confirmed the Lys5* to be 'homozygous' in the proband.

Phenotypes include:
severe ID, muscular hypotonia, sensorineural hearing impairment, microcephaly, nystagmus, seizures, hypoplastic corpus callous, neonatal low GGT cholesatsis, hepatomegaly, failure to thrive
Mendeliome v1.1860 SERPINA11 Ain Roesley Marked gene: SERPINA11 as ready
Mendeliome v1.1860 SERPINA11 Ain Roesley Gene: serpina11 has been classified as Red List (Low Evidence).
Mendeliome v1.1860 SERPINA11 Ain Roesley Phenotypes for gene: SERPINA11 were changed from to pericardial effusion; pleural effusion
Mendeliome v1.1859 SERPINA11 Ain Roesley edited their review of gene: SERPINA11: Changed phenotypes: pericardial effusion, pleural effusion
Mendeliome v1.1859 SERPINA11 Ain Roesley gene: SERPINA11 was added
gene: SERPINA11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SERPINA11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SERPINA11 were set to 38831697
Review for gene: SERPINA11 was set to RED
gene: SERPINA11 was marked as current diagnostic
Added comment: 1 family with 2 fetuses.

1st fetus presented with isolated pericardial effusion and a TOP was opted.
post mortem:
mild subcutaneous edema with subtle facial dysmorphic features
small gelatinous glistening cyst on the right pericardium. Bilateral pleural effusion and multiple similar cysts were noted on the lung surfaces

2nd fetus also presented with pleural and pericardial effusion and a TOP was opted
post mortem findings were similar to fetus#1

homozygous nonsense variant in SERPINA11 was found p.(Tyr224*)

Immunofluorescence of lung sections from fetus#1 and a gestation-matched fetus as a control demonstrated undetectable levels of SERPINA11 in the bronchiolar epithelium
Sources: Literature
Mendeliome v1.1858 PSMD11 Bryony Thompson Marked gene: PSMD11 as ready
Mendeliome v1.1858 PSMD11 Bryony Thompson Gene: psmd11 has been classified as Green List (High Evidence).
Mendeliome v1.1858 PSMD11 Bryony Thompson Classified gene: PSMD11 as Green List (high evidence)
Mendeliome v1.1858 PSMD11 Bryony Thompson Gene: psmd11 has been classified as Green List (High Evidence).
Mendeliome v1.1857 PSMD11 Bryony Thompson gene: PSMD11 was added
gene: PSMD11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMD11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PSMD11 were set to 38866022; 30733659
Phenotypes for gene: PSMD11 were set to Neurodevelopmental disorder, MONDO:0700092, PSMD11-related
Review for gene: PSMD11 was set to GREEN
Added comment: PMID: 38866022 - 10 unrelated children with early-onset syndromic intellectual disability and neurodevelopmental delay with recurrent obesity. Cognitive impairment is recapitulated in a drosophila model. Loss of function is the mechanism of disease

PMID: 30733659 - 4 probands with ID and different 17q11.2 deletions spanning PSMD11
Sources: Literature
Mendeliome v1.1856 VPS50 Ain Roesley Classified gene: VPS50 as Green List (high evidence)
Mendeliome v1.1856 VPS50 Ain Roesley Gene: vps50 has been classified as Green List (High Evidence).
Mendeliome v1.1855 VPS50 Ain Roesley changed review comment from: 1x proband Chet for a nonsense p.(Lys5*) and a complex structural variant of a 4.3Mb inversion, flanked by 170kb and 428kb deletions, respectively. The 428kb deletion spans the entire VPS50 gene.

Sanger confirmed the Lys5* to be 'homozygous' in the proband.

Phenotypes include:
nystagmus, seizures, hypoplastic corpus callous, neonatal low GGT cholesatsis, hepatomegaly, failure to thrive; to: 1x proband Chet for a nonsense p.(Lys5*) and a complex structural variant of a 4.3Mb inversion, flanked by 170kb and 428kb deletions, respectively. The 428kb deletion spans the entire VPS50 gene.

Sanger confirmed the Lys5* to be 'homozygous' in the proband.

Phenotypes include:
microcephaly, nystagmus, seizures, hypoplastic corpus callous, neonatal low GGT cholesatsis, hepatomegaly, failure to thrive
Mendeliome v1.1855 VPS50 Ain Roesley reviewed gene: VPS50: Rating: GREEN; Mode of pathogenicity: None; Publications: 38876772; Phenotypes: Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis MIM#619685; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1855 C10orf71 Sangavi Sivagnanasundram gene: C10orf71 was added
gene: C10orf71 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: C10orf71 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: C10orf71 were set to 38950288
Phenotypes for gene: C10orf71 were set to dilated cardiomyopathy MONDO:0005021
Review for gene: C10orf71 was set to GREEN
Added comment: Identified a frameshift variant in a large multigenerational family with 8 affected individuals.
Further identified four other loss of function variants in a large Chinese cohort of sporadic DCM cases. >50 unrelated individuals identified with loss of function variants.

c10orf71-Knockout mouse model recapitulating DCM human phenotype (impairs cardiac function) in the presence of the frameshift variant.
Sources: Other
Mendeliome v1.1855 PAK2 Ain Roesley Publications for gene: PAK2 were set to 33693784
Mendeliome v1.1854 PAK2 Ain Roesley Classified gene: PAK2 as Green List (high evidence)
Mendeliome v1.1854 PAK2 Ain Roesley Gene: pak2 has been classified as Green List (High Evidence).
Mendeliome v1.1853 PAK2 Ain Roesley reviewed gene: PAK2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38894571, 38712026; Phenotypes: Knobloch syndrome 2 MIM#618458; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1853 USP25 Sangavi Sivagnanasundram gene: USP25 was added
gene: USP25 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: USP25 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: USP25 were set to 38875478
Phenotypes for gene: USP25 were set to USP25-related epilepsy (epilepsy, idiopathic generalized, MONDO:0005579)
Mode of pathogenicity for gene: USP25 was set to Other
Review for gene: USP25 was set to GREEN
Added comment: PMID: 38875478
5 heterozygous variants were identified in 8 individuals from 5 unrelated families all with clinical phenotypes associated with generalised epilepsy.

Knock-out mouse model showed increased seizure susceptibility compared to the WT.
Both loss of function and gain of function variants can be a mechanism of disease in individuals with USP25-related epilepsy.
Sources: Other
Mendeliome v1.1853 RTN2 Zornitza Stark Phenotypes for gene: RTN2 were changed from Spastic paraplegia 12, autosomal dominant, 604805; MONDO:0011489; distal hereditary motor neuropathy, MONDO:0018894 to Spastic paraplegia 12, autosomal dominant, 604805; MONDO:0011489; Neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticity, MIM# 620854
Mendeliome v1.1852 RBFOX3 Zornitza Stark Marked gene: RBFOX3 as ready
Mendeliome v1.1852 RBFOX3 Zornitza Stark Gene: rbfox3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1852 RBFOX3 Zornitza Stark Classified gene: RBFOX3 as Amber List (moderate evidence)
Mendeliome v1.1852 RBFOX3 Zornitza Stark Gene: rbfox3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1851 RBFOX3 Zornitza Stark gene: RBFOX3 was added
gene: RBFOX3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RBFOX3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RBFOX3 were set to 35951651; 36117209; 24039908
Phenotypes for gene: RBFOX3 were set to Neurodevelopmental disorder (MONDO:0700092), RBFOX3-related
Review for gene: RBFOX3 was set to AMBER
Added comment: Reported as a candidate gene for epilepsy, particularly Rolandic epilepsy. Two supportive animal models.
Sources: Literature
Mendeliome v1.1850 GRXCR2 Zornitza Stark Publications for gene: GRXCR2 were set to 24619944
Mendeliome v1.1849 GRXCR2 Zornitza Stark Mode of inheritance for gene: GRXCR2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1848 GRXCR2 Zornitza Stark Classified gene: GRXCR2 as Green List (high evidence)
Mendeliome v1.1848 GRXCR2 Zornitza Stark Gene: grxcr2 has been classified as Green List (High Evidence).
Mendeliome v1.1847 GRXCR2 Zornitza Stark edited their review of gene: GRXCR2: Added comment: PMID:33528103 reported another family and an unrelated individual from Cameroon with a different homozygous variant (c.251delC/ p.Ile85SerfsTer33).; Changed rating: GREEN; Changed publications: 24619944, 33528103
Mendeliome v1.1847 THBS2 Zornitza Stark Phenotypes for gene: THBS2 were changed from {Lumbar disc herniation, susceptibility to} 603932; connective tissue disorder MONDO:0003900, THBS2-related to Ehlers-Danlos syndrome, classic type, 3, MIM# 620865
Mendeliome v1.1846 ERBB4 Zornitza Stark changed review comment from: ALS: at least 4 families reported with SNVs.

ID: intragenic deletions in 3 families, some inherited.; to: ALS: at least 4 families reported with SNVs, but LIMITED by ClinGen.

ID: intragenic deletions in 3 families, some inherited. Unclear if SNVs cause phenotype.
Mendeliome v1.1846 ERBB4 Zornitza Stark edited their review of gene: ERBB4: Changed rating: AMBER
Mendeliome v1.1846 MTSS1L Ain Roesley Phenotypes for gene: MTSS1L were changed from ntellectual developmental disorder with ocular anomalies and distinctive facial features MIM#620086 to Intellectual developmental disorder with ocular anomalies and distinctive facial features MIM#620086
Mendeliome v1.1845 MTSS1L Ain Roesley Phenotypes for gene: MTSS1L were changed from Intellectual disability, MTSS2-related (MONDO#0001071) to ntellectual developmental disorder with ocular anomalies and distinctive facial features MIM#620086
Mendeliome v1.1844 MTCL1 Zornitza Stark Mode of inheritance for gene: MTCL1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1843 ZNF292 Ain Roesley Phenotypes for gene: ZNF292 were changed from Intellectual developmental disorder, autosomal dominant 63, MIM# 619188; Intellectual disability; Autism; ADHD to Intellectual developmental disorder, autosomal dominant 64 MIM#619188
Mendeliome v1.1842 MYH10 Zornitza Stark Phenotypes for gene: MYH10 were changed from Microcephaly; Intellectual Disability to AD complex neurodevelopmental disorder with or without congenital anomalies (MONDO:0100465)
Mendeliome v1.1841 FUZ Zornitza Stark Mode of inheritance for gene: FUZ was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1840 THRB Achchuthan Shanmugasundram reviewed gene: THRB: Rating: AMBER; Mode of pathogenicity: None; Publications: 37547476; Phenotypes: inherited retinal dystrophy, MONDO:0019118; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1840 SUMF1 Achchuthan Shanmugasundram changed review comment from: PMID:38863195 reported three unrelated cases with biallelic SUMF1 variants and retinal dystrophy. One of them was a paediatric patient with an attenuated phenotype, while the other two are adult patients with non-syndromic retinal dystrophy.; to: PMID:38863195 reported three unrelated cases with biallelic SUMF1 variants and retinal dystrophy. One of them was a paediatric patient with an attenuated phenotype, while the other two are adult patients with non-syndromic retinal dystrophy.

Retinal dystrophy is part of the multiple sulfatase deficiency phenotype (MIM #272200) typically associated with biallelic variants in SUMF1, and these cases show that presumed hypomorphic variants in SUMF1 may also be associated with non-syndromic retinal dystrophy.
Mendeliome v1.1840 SUMF1 Achchuthan Shanmugasundram reviewed gene: SUMF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38863195; Phenotypes: inherited retinal dystrophy, MONDO:0019118; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1840 PRRX1 Melanie Marty changed review comment from: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)
> Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import.

Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651)

>Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708). Authors of the more recent publication on Craniosynostosis (PMID: 37154149) cast some doubt on the reports for Agnathia-otocephaly, possible explanations discussed are that this condition is AR and a 2nd hit was missed or another cause was not identified such as variants in OTX2.

> PMID: 7758948 generated a loss-of-function mutation in the mouse Pmx1 gene. Mice homozygous for the mutant allele died soon after birth and exhibited defects of skeletogenesis, which involved the loss or malformation of craniofacial, limb, and vertebral skeletal structures. ; to: Craniosynostosis (MONDO:0015469), PRRX1-related
> 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)
> Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import.

Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651)

Agnathia-otocephaly complex, MIM# 202650
>Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708). Authors of the more recent publication on Craniosynostosis (PMID: 37154149) cast some doubt on the reports for Agnathia-otocephaly, possible explanations discussed are that this condition is AR and a 2nd hit was missed or another cause was not identified such as variants in OTX2.

> PMID: 7758948 generated a loss-of-function mutation in the mouse Pmx1 gene. Mice homozygous for the mutant allele died soon after birth and exhibited defects of skeletogenesis, which involved the loss or malformation of craniofacial, limb, and vertebral skeletal structures.
Mendeliome v1.1840 PRRX1 Melanie Marty changed review comment from: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)
> Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import.

Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651)

>Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708). Authors of the more recent publication on Craniosynostosis (PMID: 37154149) cast some doubt on the reports for Agnathia-otocephaly, possible explanations discussed are that this condition is AR and a 2nd hit was missed or another cause was not identified such as variants in OTX2.; to: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)
> Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import.

Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651)

>Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708). Authors of the more recent publication on Craniosynostosis (PMID: 37154149) cast some doubt on the reports for Agnathia-otocephaly, possible explanations discussed are that this condition is AR and a 2nd hit was missed or another cause was not identified such as variants in OTX2.

> PMID: 7758948 generated a loss-of-function mutation in the mouse Pmx1 gene. Mice homozygous for the mutant allele died soon after birth and exhibited defects of skeletogenesis, which involved the loss or malformation of craniofacial, limb, and vertebral skeletal structures.
Mendeliome v1.1840 PRRX1 Melanie Marty changed review comment from: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)
> Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import.

Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651)

>Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708).; to: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)
> Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import.

Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651)

>Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708). Authors of the more recent publication on Craniosynostosis (PMID: 37154149) cast some doubt on the reports for Agnathia-otocephaly, possible explanations discussed are that this condition is AR and a 2nd hit was missed or another cause was not identified such as variants in OTX2.
Mendeliome v1.1840 PRRX1 Melanie Marty changed review comment from: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)
> Authors discuss how the previous reports of agnathia-otocephaly doen't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import.

Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651)

>Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708).; to: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)
> Authors discuss how the previous reports of agnathia-otocephaly doesn't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import.

Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651)

>Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708).
Mendeliome v1.1840 PRRX1 Melanie Marty changed review comment from: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)
> Authors discuss how the previous reports of agnathia-otocephaly don't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import.


Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651); to: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)
> Authors discuss how the previous reports of agnathia-otocephaly doen't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import.

Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651)

>Agnathia-otocephaly complex, 2 x missense variants (1 x het, 1 x hom) and 2 x frameshifts reported (het). The frameshift variants both occur in a poly A tract (PMID: 21294718, PMID: 22674740, PMID: 23444262, PMID: 22211708).
Mendeliome v1.1840 PRRX1 Melanie Marty changed review comment from: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)

Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651); to: > 17 individuals with Craniosynostosis from 14 families had been found to have rare heterozygous variants in PRRX1, loss of function variants (PTCs, start loss and partial/full gene del) or missense variants affecting the homeodomain.
> These consisted of three de novo variants, but for the majority of cases the variant was inherited from an unaffected parent, yielding an estimate for the penetrance of craniosynostosis of 12.5%.
> These results were also supported by immunofluorescence analyses which showed that missense variants within the PRRX1 homeodomain cause abnormal nuclear localisation (PMID: 37154149)
> Authors discuss how the previous reports of agnathia-otocephaly don't fit with this new evidence and they showed that a missense variant previously reported in a patient with agnathia-otocephaly p.(Phe113Leu) did not affect nuclear import.


Supporting evidence:
> Post-natal calvarial stem cells expressing Prrx1 have been shown to reside exclusively in the calvarial suture niche, suggesting a requirement for PRRX1 regarding suture patency during early development (PMID: 28366454)

>Prrx1 has been shown to be widely expressed within the mouse coronal suture (PMID: 34376651)
Mendeliome v1.1840 PRRX1 Melanie Marty reviewed gene: PRRX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37154149, 28366454, 34376651; Phenotypes: Craniosynostosis (MONDO:0015469), PRRX1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1840 AFF2 Zornitza Stark Phenotypes for gene: AFF2 were changed from Mental retardation, X-linked, FRAXE type 309548 to Intellectual disability, X-linked, FRAXE type, MIM#309548
Mendeliome v1.1839 AFF2 Zornitza Stark Mode of inheritance for gene: AFF2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.1838 AFF2 Zornitza Stark edited their review of gene: AFF2: Changed phenotypes: Intellectual disability, X-linked, FRAXE type 309548; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.1838 RDH14 Zornitza Stark Marked gene: RDH14 as ready
Mendeliome v1.1838 RDH14 Zornitza Stark Gene: rdh14 has been classified as Red List (Low Evidence).
Mendeliome v1.1838 RDH14 Zornitza Stark gene: RDH14 was added
gene: RDH14 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RDH14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RDH14 were set to 34848785
Phenotypes for gene: RDH14 were set to Neurodevelopmental disorder, MONDO:0700092, RDH14-related
Review for gene: RDH14 was set to RED
Added comment: Two related individuals with ID and cerebellar atrophy and homozygous LoF variant reported.
Sources: Literature
Mendeliome v1.1837 HYKK Zornitza Stark Marked gene: HYKK as ready
Mendeliome v1.1837 HYKK Zornitza Stark Gene: hykk has been classified as Red List (Low Evidence).
Mendeliome v1.1837 HYKK Zornitza Stark gene: HYKK was added
gene: HYKK was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HYKK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HYKK were set to 23242558
Phenotypes for gene: HYKK were set to inborn disorder of lysine and hydroxylysine metabolism MONDO:0017351
Review for gene: HYKK was set to RED
Added comment: No known gene-disease association as classified by ClinGen Aminoacidopathy GCEP on 14/07/2023 - https://search.clinicalgenome.org/CCID:005104 HYKK has been reported as a disorders of lysine, hydroxylysine, and tryptophan metabolism by ICIMD however there are no reported pathogenic variants in this gene to support the gene-disease association.
Sources: Literature
Mendeliome v1.1836 KMO Zornitza Stark Marked gene: KMO as ready
Mendeliome v1.1836 KMO Zornitza Stark Gene: kmo has been classified as Red List (Low Evidence).
Mendeliome v1.1836 KMO Zornitza Stark gene: KMO was added
gene: KMO was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KMO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KMO were set to 28187857; 24189070
Phenotypes for gene: KMO were set to pellagra MONDO:0019975
Review for gene: KMO was set to RED
Added comment: Classified as no known disease relationship by ClinGen Aminoacidopathy GCEP on 12/05/2023 - https://search.clinicalgenome.org/CCID:005248 Only two knock out mouse models have ben reported that exhibited behavioural changes including memory impairment and anxiety like behaviour. Not reported as disease causing in any affected individuals at this stage and no evidence of any inborn errors of amino acid metabolism.
Sources: Literature
Mendeliome v1.1835 FUZ Zornitza Stark Phenotypes for gene: FUZ were changed from {Neural tube defects, susceptibility to} MIM#182940; craniosynostosis, FUZ-related MONDO#0015469 to {Neural tube defects, susceptibility to} MIM#182940; craniosynostosis, FUZ-related MONDO#0015469; Ciliopathy_MONDO_0005308, FUZ-related; skeletal ciliopathy
Mendeliome v1.1834 FUZ Zornitza Stark Publications for gene: FUZ were set to 21840926
Mendeliome v1.1833 ATXN7L3 Zornitza Stark Marked gene: ATXN7L3 as ready
Mendeliome v1.1833 ATXN7L3 Zornitza Stark Gene: atxn7l3 has been classified as Green List (High Evidence).
Mendeliome v1.1833 ATXN7L3 Zornitza Stark Phenotypes for gene: ATXN7L3 were changed from Neurodevelopmental disorder, MONDO_0100500 to Neurodevelopmental disorder, MONDO_0100500, ATXN7L3-related
Mendeliome v1.1832 STK33 Zornitza Stark Marked gene: STK33 as ready
Mendeliome v1.1832 STK33 Zornitza Stark Gene: stk33 has been classified as Red List (Low Evidence).
Mendeliome v1.1832 STK33 Zornitza Stark gene: STK33 was added
gene: STK33 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STK33 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STK33 were set to 34155512; 29155043
Phenotypes for gene: STK33 were set to Spermatogenic failure 93, MIM#620849
Review for gene: STK33 was set to RED
Added comment: Four brothers with a homozygous variant and an animal model.
Sources: Literature
Mendeliome v1.1831 NAT6 Zornitza Stark Marked gene: NAT6 as ready
Mendeliome v1.1831 NAT6 Zornitza Stark Gene: nat6 has been classified as Red List (Low Evidence).
Mendeliome v1.1831 NAT6 Zornitza Stark gene: NAT6 was added
gene: NAT6 was added to Mendeliome. Sources: Literature
new gene name tags were added to gene: NAT6.
Mode of inheritance for gene: NAT6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAT6 were set to 34805998
Phenotypes for gene: NAT6 were set to Auroneurodental syndrome, MIM# 620830
Review for gene: NAT6 was set to RED
Added comment: Case report of two brothers with homozygous missense variant and deafness, periodic hypotonia and dental anomalies.

HGNC approved name is NAA80.
Sources: Literature
Mendeliome v1.1830 FAM177A1 Zornitza Stark Marked gene: FAM177A1 as ready
Mendeliome v1.1830 FAM177A1 Zornitza Stark Gene: fam177a1 has been classified as Green List (High Evidence).
Mendeliome v1.1830 FAM177A1 Zornitza Stark Phenotypes for gene: FAM177A1 were changed from Neurodevelopmental disorder, MONDO_0100500 to Neurodevelopmental disorder, MONDO_0100500, FAM177A1-related
Mendeliome v1.1829 ERF Zornitza Stark Phenotypes for gene: ERF were changed from Craniosynostosis 4, MIM# 600775; Chitayat syndrome, MIM# 617180 to Craniosynostosis 4, MIM# 600775; Chitayat syndrome, MIM# 617180; Noonan syndrome-like, MONDO:0018997, with or without craniosynostosis, ERF-related
Mendeliome v1.1828 ERF Zornitza Stark edited their review of gene: ERF: Changed phenotypes: Craniosynostosis 4, MIM# 600775, Chitayat syndrome, MIM# 617180, Noonan syndrome-like, MONDO:0018997, with or without craniosynostosis, ERF-related
Mendeliome v1.1828 MSL2 Zornitza Stark Phenotypes for gene: MSL2 were changed from Developmental disorders; autism to Neurodevelopmental disorder, MONDO:0700092, MSL2-related
Mendeliome v1.1827 MSL2 Zornitza Stark Publications for gene: MSL2 were set to 31332282; 33057194
Mendeliome v1.1826 MSL2 Zornitza Stark Classified gene: MSL2 as Green List (high evidence)
Mendeliome v1.1826 MSL2 Zornitza Stark Gene: msl2 has been classified as Green List (High Evidence).
Mendeliome v1.1825 HGF Zornitza Stark Phenotypes for gene: HGF were changed from Deafness, autosomal recessive 39, MIM# 608265 to Deafness, autosomal recessive 39, MIM# 608265; Lymphoedema, MONDO:0019297, HGF-related
Mendeliome v1.1824 HGF Zornitza Stark Publications for gene: HGF were set to 19576567
Mendeliome v1.1823 HGF Zornitza Stark Mode of inheritance for gene: HGF was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1822 HGF Zornitza Stark edited their review of gene: HGF: Added comment: More than 10 families reported with childhood- to late-onset lymphoedema.; Changed publications: 19576567, 38676400, 38791500; Changed phenotypes: Deafness, autosomal recessive 39, MIM# 608265, Lymphoedema, MONDO:0019297, HGF-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1822 TKFC Zornitza Stark Phenotypes for gene: TKFC were changed from Triokinase and FMN cyclase deficiency syndrome, MIM#618805; Developmental delay; cataracts; liver dysfunction to Triokinase and FMN cyclase deficiency syndrome, MIM#618805; Inborn error of immunity, MONDO:0003778, TKFC-related
Mendeliome v1.1821 TKFC Zornitza Stark edited their review of gene: TKFC: Added comment: Single individual reported with homozygous variant and isolated immunodeficiency.; Changed publications: 32004446'38697782; Changed phenotypes: Triokinase and FMN cyclase deficiency syndrome, MIM#618805, Inborn error of immunity, MONDO:0003778, TKFC-related
Mendeliome v1.1821 CYLC1 Zornitza Stark Marked gene: CYLC1 as ready
Mendeliome v1.1821 CYLC1 Zornitza Stark Gene: cylc1 has been classified as Green List (High Evidence).
Mendeliome v1.1821 CYLC1 Zornitza Stark Classified gene: CYLC1 as Green List (high evidence)
Mendeliome v1.1821 CYLC1 Zornitza Stark Gene: cylc1 has been classified as Green List (High Evidence).
Mendeliome v1.1820 CYLC1 Zornitza Stark gene: CYLC1 was added
gene: CYLC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CYLC1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: CYLC1 were set to Spermatogenic failure, X-linked, 8, MIM# 301119
Review for gene: CYLC1 was set to GREEN
Added comment: 19 individuals and a mouse model reported.
Sources: Literature
Mendeliome v1.1819 FLT3LG Ain Roesley Marked gene: FLT3LG as ready
Mendeliome v1.1819 FLT3LG Ain Roesley Gene: flt3lg has been classified as Red List (Low Evidence).
Mendeliome v1.1819 FLT3LG Ain Roesley gene: FLT3LG was added
gene: FLT3LG was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FLT3LG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLT3LG were set to 38701783
Phenotypes for gene: FLT3LG were set to Increased susceptibility to infections
Review for gene: FLT3LG was set to RED
gene: FLT3LG was marked as current diagnostic
Added comment: 3x sibs from a consanguineous family with a homozygous frameshift variant p.(Ser118Alafs*23)
recurrent infections and hypoplastic bone marrow with marked reduction in HPSCs
KO mice recapitulated BM findings

over a period of 5 (P1), 9 (P2), and 19 (P3) years of follow-up, all 3 were found to have moderate anaemia.
Total platelet counts and morphology decreased in 2 siblings.
Total WBC oscillated between low and normal
Eosinophils, basophils were in normal range
Neutrophils were in the lower part of the control range, ocassiannly lower
total lymphocyte counts were normal
Sources: Literature
Mendeliome v1.1818 TIE1 Ain Roesley Classified gene: TIE1 as Green List (high evidence)
Mendeliome v1.1818 TIE1 Ain Roesley Gene: tie1 has been classified as Green List (High Evidence).
Mendeliome v1.1818 TIE1 Ain Roesley Publications for gene: TIE1 were set to 32947856; 24764452
Mendeliome v1.1817 TIE1 Ain Roesley reviewed gene: TIE1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38820174; Phenotypes: Lymphatic malformation 11, MIM# 619401; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1817 MSL2 Sangavi Sivagnanasundram reviewed gene: MSL2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38815585, 38702431; Phenotypes: MSL2-Related Developmental Disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1817 PISD Sangavi Sivagnanasundram reviewed gene: PISD: Rating: GREEN; Mode of pathogenicity: None; Publications: 38801004; Phenotypes: Liberfarb syndrome MONDO:0030045; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1817 ATXN7L3 Chirag Patel Classified gene: ATXN7L3 as Green List (high evidence)
Mendeliome v1.1817 ATXN7L3 Chirag Patel Gene: atxn7l3 has been classified as Green List (High Evidence).
Mendeliome v1.1816 ATXN7L3 Chirag Patel gene: ATXN7L3 was added
gene: ATXN7L3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATXN7L3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATXN7L3 were set to PMID: 38753057
Phenotypes for gene: ATXN7L3 were set to Neurodevelopmental disorder, MONDO_0100500
Review for gene: ATXN7L3 was set to GREEN
gene: ATXN7L3 was marked as current diagnostic
Added comment: This study reports 9 unrelated individuals with de novo heterozygous variants in ATXN7L3 identified through WES testing and GeneMatcher. Core clinical features included: global motor and language developmental delay, hypotonia, and dysmorphic features (hypertelorism, epicanthal folds, blepharoptosis, small nose, small mouth, and low-set posteriorly rotated ears). Variable features included: feeding difficulties, seizures, mild periventricular leukomalacia, and structural cardiac abnormalities.

A recurrent nonsense variant [p.(Arg114Ter)] was found in 5/9 individuals. The other variants were 1 frameshift [p.(Ser112LysfsTer12)] and 3 missense variants [p.(Ile71Thr), p.(Ser92Arg), and p.(Leu106Pro)]. They investigated the effects of the recurrent nonsense variant [p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired (as indicated by an increase in histone H2Bub1 levels). This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality.

Pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders (ND) and congenital abnormalities. ATXN7L3 is a component of the DUB module of the SAGA complex, and two other related DUB modules, and serves as an obligate adaptor protein of 3 ubiquitin-specific proteases (USP22, USP27X or USP51).
Sources: Literature
Mendeliome v1.1815 FAM177A1 Chirag Patel Classified gene: FAM177A1 as Green List (high evidence)
Mendeliome v1.1815 FAM177A1 Chirag Patel Gene: fam177a1 has been classified as Green List (High Evidence).
Mendeliome v1.1814 FAM177A1 Chirag Patel gene: FAM177A1 was added
gene: FAM177A1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FAM177A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM177A1 were set to PMID: 38767059, 25558065
Phenotypes for gene: FAM177A1 were set to Neurodevelopmental disorder, MONDO_0100500
Review for gene: FAM177A1 was set to GREEN
gene: FAM177A1 was marked as current diagnostic
Added comment: PMID: 38767059
5 individuals from 3 unrelated families reported with with biallelic loss of function variants in FAM177A1. Clinical features included: global developmental delay, intellectual disability, seizures, behavioural abnormalities, hypotonia, gait disturbance, and macrocephaly.

They showed that FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells. Intersection of the RNA-seq and metabolomic datasets from FAM177A1-deficient human fibroblasts and whole zebrafish larvae demonstrated dysregulation of pathways associated with apoptosis, inflammation, and negative regulation of cell proliferation.

PMID: 25558065
A study of 143 multiplex consanguineous families identified a homozygous frameshift variant in FAM177A1 in 1 family with 4 affected siblings with intellectual disability, dolicocephaly, obesity, and macrocephaly. The variant segregated with all 4 affected siblings and parents were confirmed heterozygous carriers.
Sources: Literature
Mendeliome v1.1813 ERF Chirag Patel reviewed gene: ERF: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38824261; Phenotypes: Noonan syndrome-like with or without craniosynostosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1813 SLC6A1 Sangavi Sivagnanasundram reviewed gene: SLC6A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38781976; Phenotypes: myoclonic-atonic epilepsy MONDO:0014633; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1813 FUZ Chirag Patel Classified gene: FUZ as Green List (high evidence)
Mendeliome v1.1813 FUZ Chirag Patel Gene: fuz has been classified as Green List (High Evidence).
Mendeliome v1.1812 ANO4 Ain Roesley Marked gene: ANO4 as ready
Mendeliome v1.1812 ANO4 Ain Roesley Gene: ano4 has been classified as Green List (High Evidence).
Mendeliome v1.1812 ANO4 Ain Roesley Classified gene: ANO4 as Green List (high evidence)
Mendeliome v1.1812 ANO4 Ain Roesley Gene: ano4 has been classified as Green List (High Evidence).
Mendeliome v1.1811 FUZ Chirag Patel reviewed gene: FUZ: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38702430, 29068549, 34719684; Phenotypes: Ciliopathy_MONDO_0005308, skeletal ciliopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1811 ANO4 Ain Roesley Classified gene: ANO4 as Green List (high evidence)
Mendeliome v1.1811 ANO4 Ain Roesley Gene: ano4 has been classified as Green List (High Evidence).
Mendeliome v1.1810 ANO4 Ain Roesley gene: ANO4 was added
gene: ANO4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ANO4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANO4 were set to 38744284
Phenotypes for gene: ANO4 were set to neurodevelopmental disorder MONDO:0700092, ANO4-related
Review for gene: ANO4 was set to GREEN
gene: ANO4 was marked as current diagnostic
Added comment: aka TMEM16D

5x de novo + 2x inherited missense (73% penetrance + asymptomatic)

the ones with de novo variants:
all had ID, hypotonia
4x skeletal features (scoliosis, funnel chest, pet plants, hyper extensible joints)

all had epilepsy
all had abnormal MRI
Sources: Literature
Mendeliome v1.1809 KCND1 Ain Roesley Marked gene: KCND1 as ready
Mendeliome v1.1809 KCND1 Ain Roesley Gene: kcnd1 has been classified as Green List (High Evidence).
Mendeliome v1.1809 KCND1 Ain Roesley Classified gene: KCND1 as Green List (high evidence)
Mendeliome v1.1809 KCND1 Ain Roesley Gene: kcnd1 has been classified as Green List (High Evidence).
Mendeliome v1.1808 KCND1 Ain Roesley gene: KCND1 was added
gene: KCND1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCND1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: KCND1 were set to 38772379
Phenotypes for gene: KCND1 were set to neurodevelopmental disorder MONDO:0700092, KCND1-related
Review for gene: KCND1 was set to GREEN
gene: KCND1 was marked as current diagnostic
Added comment: 18 males from 17 families
2x de novo missense + 3x maternal NMDs + 12x maternal missense
Some functional studies were done

14x ID
4x delayed motor dev
7x muscular hypotonia
6x epilepsy
Sources: Literature
Mendeliome v1.1807 PPFIA3 Zornitza Stark Publications for gene: PPFIA3 were set to 37034625
Mendeliome v1.1806 PPFIA3 Zornitza Stark edited their review of gene: PPFIA3: Changed publications: 38723631
Mendeliome v1.1806 LRRC23 Zornitza Stark Phenotypes for gene: LRRC23 were changed from Non-syndromic male infertility due to sperm motility disorder, (MONDO:0017173), LRRC23-related to Spermatogenic failure 92, MIM# 620848
Mendeliome v1.1805 LRRC23 Zornitza Stark Publications for gene: LRRC23 were set to 37804054
Mendeliome v1.1804 LRRC23 Zornitza Stark Classified gene: LRRC23 as Amber List (moderate evidence)
Mendeliome v1.1804 LRRC23 Zornitza Stark Gene: lrrc23 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1803 LRRC23 Zornitza Stark reviewed gene: LRRC23: Rating: AMBER; Mode of pathogenicity: None; Publications: 38091523; Phenotypes: Spermatogenic failure 92, MIM# 620848; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1803 POLD1 Zornitza Stark Phenotypes for gene: POLD1 were changed from Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, MIM# 615381; MONDO:0014157; Combined immunodeficiency, MONDO:0015131, POLD1-related to Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, MIM# 615381; MONDO:0014157; Immunodeficiency 120, MIM# 620836
Mendeliome v1.1802 POLD1 Zornitza Stark edited their review of gene: POLD1: Changed phenotypes: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, MIM# 615381, MONDO:0014157, Immunodeficiency 120, MIM# 620836
Mendeliome v1.1802 ICOSLG Zornitza Stark Phenotypes for gene: ICOSLG were changed from Combined immunodeficiency; recurrent bacterial and viral infections; neutropaenia to Immunodeficiency 119, MIM# 620825; Combined immunodeficiency; recurrent bacterial and viral infections; neutropaenia
Mendeliome v1.1801 ICOSLG Zornitza Stark edited their review of gene: ICOSLG: Changed phenotypes: Immunodeficiency 119, MIM# 620825, Combined immunodeficiency, recurrent bacterial and viral infections, neutropaenia
Mendeliome v1.1801 SYCP2L Zornitza Stark Phenotypes for gene: SYCP2L were changed from Premature ovarian insufficiency to Premature ovarian failure 24, MIM# 620840
Mendeliome v1.1800 GABRA4 Zornitza Stark Phenotypes for gene: GABRA4 were changed from Developmental and epileptic encephalopathy MONDO:0100062, GABRA4-related to Neurodevelopmental disorder MONDO:0700092, GABRA4-related
Mendeliome v1.1799 GABRA4 Zornitza Stark Publications for gene: GABRA4 were set to 35152403
Mendeliome v1.1798 GABRA4 Zornitza Stark Classified gene: GABRA4 as Green List (high evidence)
Mendeliome v1.1798 GABRA4 Zornitza Stark Gene: gabra4 has been classified as Green List (High Evidence).
Mendeliome v1.1797 GABRA4 Zornitza Stark edited their review of gene: GABRA4: Added comment: Three more novel de novo missense variants in GABRA4 (NM_000809.4): c.797 C > T, p.(Pro266Leu), c.899 C > A, p.(Thr300Asn), and c.634 G > A, p.(Val212Ile) reported.

The p.(Thr300Asn) variant impacts the same codon as the previously reported variant p.(Thr300Ile) and likely arose post-zygotically as evidenced by sequencing oral mucosal cells.

Overlapping phenotypes among affected individuals included developmental delay (4/4), epileptiform EEG abnormalities (3/4), attention deficits (3/4), seizures (2/4), autistic features (2/4) and structural brain abnormalities (2/4).; Changed rating: GREEN; Changed publications: 35152403, 38565639; Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, GABRA4-related
Mendeliome v1.1797 CCIN Zornitza Stark Phenotypes for gene: CCIN were changed from male infertility with teratozoospermia due to single gene mutation, MONDO:0018394 to Spermatogenic failure 91, MIM# 620838
Mendeliome v1.1796 CCIN Zornitza Stark reviewed gene: CCIN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spermatogenic failure 91, MIM# 620838; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1796 RBBP8 James The Deleted their review
Mendeliome v1.1796 DGCR8 Andrew Fennell reviewed gene: DGCR8: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 34821987; Phenotypes: Early-onset multinodular goiter and schwannomatosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1796 TAPBP Zornitza Stark Phenotypes for gene: TAPBP were changed from Bare lymphocyte syndrome, type I, MIM# 604571 to Bare lymphocyte syndrome, type I, MIM# 604571; MHC class I deficiency 3, MIM# 620814
Mendeliome v1.1795 TAPBP Zornitza Stark edited their review of gene: TAPBP: Changed phenotypes: Bare lymphocyte syndrome, type I, MIM# 604571, MHC class I deficiency 3, MIM# 620814
Mendeliome v1.1795 TAP2 Zornitza Stark Phenotypes for gene: TAP2 were changed from Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571; Low CD8; absent MHC I on lymphocytes; Vasculitis; pyoderma gangrenosum; recurrent bacterial/viral respiratory infections; bronchiectasis to MHC class I deficiency 2, MIM# 620813; Bare lymphocyte syndrome, type I, due to TAP2 deficiency MIM# 604571; Low CD8; absent MHC I on lymphocytes; Vasculitis; pyoderma gangrenosum; recurrent bacterial/viral respiratory infections; bronchiectasis
Mendeliome v1.1794 LIG4 Santosh Varughese reviewed gene: LIG4: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 11779494, 16088910, 15333585, 20133615; Phenotypes: LIG4 syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1794 B2M Zornitza Stark edited their review of gene: B2M: Changed phenotypes: Amyloidosis, hereditary systemic 6, MIM# 620659, Immunodeficiency 43 MIM# 241600, Sinopulmonary infections, Purple-red skin lesions, Decreased serum IgG, Decreased B cells, Absent β2m associated proteins MHC-I, CD1a, CD1b, and CD1c, MONDO:0009434, Amyloidosis, familial visceral, MIM# 105200
Mendeliome v1.1794 LYZ Zornitza Stark Phenotypes for gene: LYZ were changed from Amyloidosis, renal, MIM# 105200 to Amyloidosis, renal, MIM# 105200; Amyloidosis, hereditary systemic 5, MIM# 620658
Mendeliome v1.1793 APOA1 Zornitza Stark Phenotypes for gene: APOA1 were changed from Amyloidosis, 3 or more types MIM#105200; Hypoalphalipoproteinemia, primary, 2 MIM#618463; Hypoalphalipoproteinemia, primary, 2, intermediate MIM#619836 to Amyloidosis, hereditary systemic 3, MIM# 620657; Amyloidosis, 3 or more types MIM#105200; Hypoalphalipoproteinemia, primary, 2 MIM#618463; Hypoalphalipoproteinemia, primary, 2, intermediate MIM#619836
Mendeliome v1.1792 RBBP8 Zornitza Stark Publications for gene: RBBP8 were set to 21998596
Mendeliome v1.1791 RBBP8 Zornitza Stark edited their review of gene: RBBP8: Added comment: Additional family reported with Jawad syndrome: prev reported founder variant, multi-generational family, abnormal splicing demonstrated.; Changed rating: GREEN; Changed publications: 34270086; Changed phenotypes: Jawad syndrome, MIM# 251255; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1791 ZDHHC15 Zornitza Stark Phenotypes for gene: ZDHHC15 were changed from Mental retardation, X-linked 91, 300577; cerebral palsy; intellectual disability; autism spectrum disorder; epilepsy to Intellectual disability, X-linked 91, 300577
Mendeliome v1.1790 ZDHHC15 Zornitza Stark Tag disputed tag was added to gene: ZDHHC15.
Mendeliome v1.1790 ZDHHC15 Zornitza Stark edited their review of gene: ZDHHC15: Changed phenotypes: Intellectual disability, X-linked 91, 300577
Mendeliome v1.1790 ZNF41 Zornitza Stark Marked gene: ZNF41 as ready
Mendeliome v1.1790 ZNF41 Zornitza Stark Gene: znf41 has been classified as Red List (Low Evidence).
Mendeliome v1.1790 ZNF41 Zornitza Stark gene: ZNF41 was added
gene: ZNF41 was added to Mendeliome. Sources: Expert Review
disputed tags were added to gene: ZNF41.
Mode of inheritance for gene: ZNF41 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: ZNF41 were set to 14628291; 23871722
Phenotypes for gene: ZNF41 were set to non-syndromic X-linked intellectual disability MONDO:0019181
Review for gene: ZNF41 was set to RED
Added comment: DISPUTED by ClinGen.

Shoichet et al. (2003) described a female patient with severe nonsyndromic mental retardation and a de novo balanced translocation t(X;7)(p11.3;q11.21) in whom they cloned the DNA fragment that contained the X chromosomal and the autosomal breakpoint. In silico sequence analysis demonstrated that the ZNF41 gene was disrupted. Expression studies indicated that ZNF41 transcripts were absent in the patient cell line, suggesting that the mental disorder in this patient resulted from loss of functional ZNF41. Screening of patients with mental retardation led to the identification of 2 other ZNF41 mutations that were not found in healthy control individuals. Based on their finding of the mutations in ZNF41 identified by Shoichet et al. (2003) in a total of 7 males in the NHLBI Exome Variant Server, and the additional finding of truncating ZNF41 variants in 1 male and 1 female in that database, Piton et al. (2013) classified the involvement of ZNF41 in mental retardation as highly questionable.
Sources: Expert Review
Mendeliome v1.1789 RBBP8 James The reviewed gene: RBBP8: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:30561437, 34270086, 32379725; Phenotypes: Jawad syndrome, Pancreatic carcinoma, somatic, Seckel syndrome 2; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1789 SHROOM4 Zornitza Stark Phenotypes for gene: SHROOM4 were changed from Stocco dos Santos X-linked mental retardation syndrome, 300434; Intellectual disability to Congenital anomaly of the kidney and urinary tracy (CAKUT), SHROOM4-related, MONDO:0019719; epilepsy, idiopathic generalised, SHROOM4-related, MONDO:0005579
Mendeliome v1.1788 ALG9 Ain Roesley Phenotypes for gene: ALG9 were changed from Congenital disorder of glycosylation, type Il, MIM#608776; Gillessen-Kaesbach-Nishimura syndrome, MIM# 263210; Polycystic kidney disease to Congenital disorder of glycosylation, type Il, MIM#608776; Gillessen-Kaesbach-Nishimura syndrome, MIM# 263210; Polycystic kidney disease; ALG9-associated autosomal dominant polycystic kidney disease MONDO:0700000
Mendeliome v1.1787 AGTR2 Zornitza Stark Marked gene: AGTR2 as ready
Mendeliome v1.1787 AGTR2 Zornitza Stark Gene: agtr2 has been classified as Red List (Low Evidence).
Mendeliome v1.1787 AGTR2 Zornitza Stark changed review comment from: Variants in AGTR2 have been reported in individuals presenting various neurodevelopmental phenotypes, including intellectual disability, autistic features, epileptic seizures, speech delay, restlessness, and hyperactivity, as early as 2002. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, for the purposes of this curation, all of these features have been lumped into one disease entity, X-linked complex neurodevelopmental disorder. Although eight unique variants, including missense and truncating, have been reported in affected humans, the majority (six) have been ruled out from disease-causality based on high frequency in control populations (Piton et al., PMID 23871722), occurrence in unaffected males (Erdmann et al., PMID 14722754), non-segregation within a family (Bienvenu et al., PMID 12746399), and lack of enrichment in patients in a case-control study (Huang et al., PMID 16283672). Given that the two remaining variants are missense with no supporting functional evidence, and AGTR2 was the only gene sequenced in each case, the ClinGen Intellectual Disability and Autism Working Group recommended awarding 0 points for these variants. There are two AGTR2 mouse models which collectively show altered neuronal spine morphology, spatial memory impairment, delayed learning, and reduced exploratory behavior (PMIDs 18335189 and 7477267).
Sources: Expert Review; to: DISPUTED by ClinGen:

Variants in AGTR2 have been reported in individuals presenting various neurodevelopmental phenotypes, including intellectual disability, autistic features, epileptic seizures, speech delay, restlessness, and hyperactivity, as early as 2002. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, for the purposes of this curation, all of these features have been lumped into one disease entity, X-linked complex neurodevelopmental disorder. Although eight unique variants, including missense and truncating, have been reported in affected humans, the majority (six) have been ruled out from disease-causality based on high frequency in control populations (Piton et al., PMID 23871722), occurrence in unaffected males (Erdmann et al., PMID 14722754), non-segregation within a family (Bienvenu et al., PMID 12746399), and lack of enrichment in patients in a case-control study (Huang et al., PMID 16283672). Given that the two remaining variants are missense with no supporting functional evidence, and AGTR2 was the only gene sequenced in each case, the ClinGen Intellectual Disability and Autism Working Group recommended awarding 0 points for these variants. There are two AGTR2 mouse models which collectively show altered neuronal spine morphology, spatial memory impairment, delayed learning, and reduced exploratory behavior (PMIDs 18335189 and 7477267).
Sources: Expert Review
Mendeliome v1.1787 AGTR2 Zornitza Stark gene: AGTR2 was added
gene: AGTR2 was added to Mendeliome. Sources: Expert Review
disputed tags were added to gene: AGTR2.
Mode of inheritance for gene: AGTR2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: AGTR2 were set to X-linked complex neurodevelopmental disorder MONDO:0100148
Review for gene: AGTR2 was set to RED
Added comment: Variants in AGTR2 have been reported in individuals presenting various neurodevelopmental phenotypes, including intellectual disability, autistic features, epileptic seizures, speech delay, restlessness, and hyperactivity, as early as 2002. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, for the purposes of this curation, all of these features have been lumped into one disease entity, X-linked complex neurodevelopmental disorder. Although eight unique variants, including missense and truncating, have been reported in affected humans, the majority (six) have been ruled out from disease-causality based on high frequency in control populations (Piton et al., PMID 23871722), occurrence in unaffected males (Erdmann et al., PMID 14722754), non-segregation within a family (Bienvenu et al., PMID 12746399), and lack of enrichment in patients in a case-control study (Huang et al., PMID 16283672). Given that the two remaining variants are missense with no supporting functional evidence, and AGTR2 was the only gene sequenced in each case, the ClinGen Intellectual Disability and Autism Working Group recommended awarding 0 points for these variants. There are two AGTR2 mouse models which collectively show altered neuronal spine morphology, spatial memory impairment, delayed learning, and reduced exploratory behavior (PMIDs 18335189 and 7477267).
Sources: Expert Review
Mendeliome v1.1786 AVPR1A Zornitza Stark Tag disputed tag was added to gene: AVPR1A.
Mendeliome v1.1786 AVPR1A Zornitza Stark Marked gene: AVPR1A as ready
Mendeliome v1.1786 AVPR1A Zornitza Stark Gene: avpr1a has been classified as Red List (Low Evidence).
Mendeliome v1.1786 AVPR1A Zornitza Stark gene: AVPR1A was added
gene: AVPR1A was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: AVPR1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AVPR1A were set to 24924430
Phenotypes for gene: AVPR1A were set to Autism spectrum disorder MONDO:0005258
Review for gene: AVPR1A was set to RED
Added comment: DISPUTED by ClinGen:

The Arginine Vasopressin Receptor 1A (AVPR1A) was considered a candidate gene in autism spectrum disorder (ASD) based on reports focused on linkage intervals and animal models. Additionally, experimental evidence showed that AVPR1A is possibly involved in social behaviors, including affiliation and attachment (PMID: 24924430). However, these association studies were underpowered—sequencing more individuals may have identified variants of functional significance. In two studies, transmission disequilibrium between AVPR1A microsatellites and autism were found but most were not statistically significant (PMID: 12082568, 16520824). In another study, investigators screened AVPR1A exons in 125 independent autistic probands (PMID: 15098001). However, the study did not demonstrate a disease-causing variant in the coding sequence, and the authors noted that differences in AVPR1A at the amino-acid level are unlikely to confer genetic vulnerability to autism. Experimental evidence is available, but, in the absence of human genetic evidence, such data were not utilized in the scoring. In summary, there is no valid genetic evidence to support an association between AVPR1A and autism spectrum disorder.
Sources: Expert list
Mendeliome v1.1785 BCORL1 Zornitza Stark Classified gene: BCORL1 as Amber List (moderate evidence)
Mendeliome v1.1785 BCORL1 Zornitza Stark Gene: bcorl1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1784 BCORL1 Zornitza Stark edited their review of gene: BCORL1: Added comment: Classified as LIMITED by ClinGen.; Changed rating: AMBER
Mendeliome v1.1784 LCP1 Zornitza Stark Marked gene: LCP1 as ready
Mendeliome v1.1784 LCP1 Zornitza Stark Gene: lcp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1784 LCP1 Zornitza Stark Classified gene: LCP1 as Amber List (moderate evidence)
Mendeliome v1.1784 LCP1 Zornitza Stark Gene: lcp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1783 LCP1 Zornitza Stark gene: LCP1 was added
gene: LCP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LCP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LCP1 were set to 38710235
Phenotypes for gene: LCP1 were set to Bone marrow failure syndrome, MONDO:0000159, LCP1-related
Review for gene: LCP1 was set to AMBER
Added comment: 3 individuals from single kindred presenting with fevers, recurrent infections ,lymphopenia, neutropenia and thrombocytopenia. Murine model with similar phenotype. heterozygous LCP1c.740 -1G>A splice site variant hypothesized to cause dominant negative mode of inheritance
Sources: Literature
Mendeliome v1.1782 CLIC2 Zornitza Stark edited their review of gene: CLIC2: Added comment: DISPUTED by ClinGen.; Changed phenotypes: Intellectual disability, X-linked, syndromic 32, 300886
Mendeliome v1.1782 UFSP2 Zornitza Stark Publications for gene: UFSP2 were set to 33473208; 26428751; 28892125; 32755715
Mendeliome v1.1781 UFSP2 Zornitza Stark edited their review of gene: UFSP2: Added comment: PMID: 37214758:

Additional patient with spondyloepimetaphyseal dysplasia type Di Rocco:
- het missense Cys302Ser
- confirmed de novo in segregation analyses
- absent in gnomAD
- no functional studies on the missense.

Four AD missense reported in the literature so far are located in the C-term catalytic domain - 1x hip dysplasia, Beukes type and 3x spondyloepimetaphyseal dysplasia type Di Rocco.

The well reported AR missense (associated with neurodevelopmental anomalies and epilepsy) is located in the N-terminal domain possibly involved in substrate binding.; Changed publications: 33473208, 26428751, 28892125, 32755715, 37214758
Mendeliome v1.1781 CNTN6 Zornitza Stark Tag disputed tag was added to gene: CNTN6.
Mendeliome v1.1781 DPP6 Zornitza Stark Phenotypes for gene: DPP6 were changed from Mental retardation, autosomal dominant 33 (MIM#616311) to Intellectual disability, autosomal dominant 33 (MIM#616311)
Mendeliome v1.1780 DPP6 Zornitza Stark Classified gene: DPP6 as Red List (low evidence)
Mendeliome v1.1780 DPP6 Zornitza Stark Gene: dpp6 has been classified as Red List (Low Evidence).
Mendeliome v1.1779 DPP6 Zornitza Stark Tag disputed tag was added to gene: DPP6.
Mendeliome v1.1779 DPP6 Zornitza Stark edited their review of gene: DPP6: Added comment: DISPUTED by ClinGen.; Changed rating: RED; Changed phenotypes: Intellectual disability, autosomal dominant 33 (MIM#616311)
Mendeliome v1.1779 KDM5A Zornitza Stark Phenotypes for gene: KDM5A were changed from autism spectrum disorder, MONDO:0005258; Neurodevelopmental disorder MONDO:0700092, KDM5A-related to El Hayek-Chahrour neurodevelopmental syndrome, MIM# 620820; Neurodevelopmental disorder MONDO:0700092, KDM5A-related
Mendeliome v1.1778 KDM5A Zornitza Stark reviewed gene: KDM5A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: El Hayek-Chahrour neurodevelopmental syndrome, MIM# 620820; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1778 KCNIP4 Ain Roesley Marked gene: KCNIP4 as ready
Mendeliome v1.1778 KCNIP4 Ain Roesley Gene: kcnip4 has been classified as Red List (Low Evidence).
Mendeliome v1.1778 KCNIP4 Ain Roesley gene: KCNIP4 was added
gene: KCNIP4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNIP4 was set to Unknown
Publications for gene: KCNIP4 were set to 33826137
Phenotypes for gene: KCNIP4 were set to seizures; epilepsy
Review for gene: KCNIP4 was set to RED
gene: KCNIP4 was marked as current diagnostic
Added comment: single paper describing insertions of L1 retrotransposons in KCNIP4
samples were post-mortem of resected temporal cortex from individuals with idiopathic temporal lobe epilepsy

1x de novo insertion of L1 in KCNIP4 however ddPCR revealed that this did NOT alter KCNIP4 mRNA expression
Sources: Literature
Mendeliome v1.1777 CHRNA7 Ain Roesley Marked gene: CHRNA7 as ready
Mendeliome v1.1777 CHRNA7 Ain Roesley Gene: chrna7 has been classified as Red List (Low Evidence).
Mendeliome v1.1777 CHRNA7 Ain Roesley gene: CHRNA7 was added
gene: CHRNA7 was added to Mendeliome. Sources: Literature
cnv tags were added to gene: CHRNA7.
Mode of inheritance for gene: CHRNA7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHRNA7 were set to 20979196; 21596161; 21290787
Phenotypes for gene: CHRNA7 were set to intellectual disability; seizures; hypotonia
Review for gene: CHRNA7 was set to RED
gene: CHRNA7 was marked as current diagnostic
Added comment: Homozygous deletion of 15q13.3, which includes CHRNA7, causes ID, hypotonia, seizures, encephalopathy
Sources: Literature
Mendeliome v1.1776 DNA2 Zornitza Stark Phenotypes for gene: DNA2 were changed from Seckel syndrome 8, MIM#615807; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 6 MIM#615156 to Rothmund-Thomson syndrome, type 4, MIM# 620819; Seckel syndrome 8, MIM#615807; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 6 MIM#615156
Mendeliome v1.1775 DNA2 Zornitza Stark Publications for gene: DNA2 were set to 24389050; 31045292; 23352259; 25635128; 28554558
Mendeliome v1.1774 DNA2 Zornitza Stark reviewed gene: DNA2: Rating: AMBER; Mode of pathogenicity: None; Publications: 37133451; Phenotypes: Rothmund-Thomson syndrome, type 4, MIM# 620819; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1774 CCDC114 Zornitza Stark Tag new gene name tag was added to gene: CCDC114.
Mendeliome v1.1774 ARMC4 Zornitza Stark Tag new gene name tag was added to gene: ARMC4.
Mendeliome v1.1774 CCDC151 Zornitza Stark Tag new gene name tag was added to gene: CCDC151.
Mendeliome v1.1774 TTC25 Zornitza Stark Tag new gene name tag was added to gene: TTC25.
Mendeliome v1.1774 ADAMTS18 Zornitza Stark Marked gene: ADAMTS18 as ready
Mendeliome v1.1774 ADAMTS18 Zornitza Stark Gene: adamts18 has been classified as Green List (High Evidence).
Mendeliome v1.1774 ADAMTS18 Zornitza Stark Classified gene: ADAMTS18 as Green List (high evidence)
Mendeliome v1.1774 ADAMTS18 Zornitza Stark Gene: adamts18 has been classified as Green List (High Evidence).
Mendeliome v1.1773 FOXD3 Zornitza Stark Tag disputed tag was added to gene: FOXD3.
Mendeliome v1.1773 NTF4 Zornitza Stark Tag disputed tag was added to gene: NTF4.
Mendeliome v1.1773 C2orf71 Zornitza Stark Tag new gene name tag was added to gene: C2orf71.
Mendeliome v1.1773 SPATA13 Zornitza Stark Phenotypes for gene: SPATA13 were changed from primary angle-closure glaucoma to primary angle-closure glaucoma MONDO:0001868
Mendeliome v1.1772 SPATA13 Zornitza Stark Classified gene: SPATA13 as Amber List (moderate evidence)
Mendeliome v1.1772 SPATA13 Zornitza Stark Gene: spata13 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1771 WDR36 Zornitza Stark Classified gene: WDR36 as Red List (low evidence)
Mendeliome v1.1771 WDR36 Zornitza Stark Gene: wdr36 has been classified as Red List (Low Evidence).
Mendeliome v1.1770 WDR36 Zornitza Stark Tag disputed tag was added to gene: WDR36.
Mendeliome v1.1770 WDR36 Sangavi Sivagnanasundram reviewed gene: WDR36: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:006545; Phenotypes: glaucoma 1, open angle, G MONDO:0012357; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1770 SPATA13 Sangavi Sivagnanasundram reviewed gene: SPATA13: Rating: AMBER; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:006261; Phenotypes: primary angle-closure glaucoma MONDO:0001868; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1770 C2orf71 Sangavi Sivagnanasundram reviewed gene: C2orf71: Rating: ; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005738; Phenotypes: PCARE-related retinopathy MONDO:0800404; Mode of inheritance: None
Mendeliome v1.1770 NTF4 Sangavi Sivagnanasundram reviewed gene: NTF4: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005684; Phenotypes: glaucoma 1, open angle, O MONDO:0013134; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1770 FOXD3 Sangavi Sivagnanasundram reviewed gene: FOXD3: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:004877; Phenotypes: aniridia MONDO:0019172; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.1770 ADAMTS18 Sangavi Sivagnanasundram gene: ADAMTS18 was added
gene: ADAMTS18 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: ADAMTS18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS18 were set to https://search.clinicalgenome.org/CCID:004057
Phenotypes for gene: ADAMTS18 were set to microcornea-myopic chorioretinal atrophy (MONDO:0014195)
Review for gene: ADAMTS18 was set to GREEN
Added comment: Classified DEFINITIVE by ClinGen Retina GCEP on 02/03/20222 - https://search.clinicalgenome.org/CCID:004057
Sources: Other
Mendeliome v1.1770 TTC25 Sangavi Sivagnanasundram reviewed gene: TTC25: Rating: ; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005700; Phenotypes: primary ciliary dyskinesia 35 MONDO:0014910; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1770 CCDC151 Sangavi Sivagnanasundram reviewed gene: CCDC151: Rating: ; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005699; Phenotypes: primary ciliary dyskinesia 30 MONDO:0014465; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1770 ARMC4 Sangavi Sivagnanasundram reviewed gene: ARMC4: Rating: ; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:005698; Phenotypes: primary ciliary dyskinesia 23 MONDO:0014193; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1770 DNAH8 Sangavi Sivagnanasundram reviewed gene: DNAH8: Rating: ; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:004671; Phenotypes: primary ciliary dyskinesia (MONDO:0016575), spermatogenic failure 46 (MONDO:0033673); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1770 DNAH17 Sangavi Sivagnanasundram changed review comment from: Classified DEFINITIVE by ClinGen on 08/09/2022 - https://search.clinicalgenome.org/CCID:004669
Sources: Other; to: Classified DEFINITIVE by ClinGen Motile Ciliopathies GCEP on 08/09/2022 - https://search.clinicalgenome.org/CCID:004669
Sources: Other
Mendeliome v1.1770 DNAH17 Sangavi Sivagnanasundram gene: DNAH17 was added
gene: DNAH17 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: DNAH17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAH17 were set to https://search.clinicalgenome.org/CCID:004669
Phenotypes for gene: DNAH17 were set to spermatogenic failure 39 (MONDO:0032845)
Review for gene: DNAH17 was set to GREEN
Added comment: Classified DEFINITIVE by ClinGen on 08/09/2022 - https://search.clinicalgenome.org/CCID:004669
Sources: Other
Mendeliome v1.1770 SLC52A1 Bryony Thompson Classified gene: SLC52A1 as Amber List (moderate evidence)
Mendeliome v1.1770 SLC52A1 Bryony Thompson Added comment: Comment on list classification: Moderate gene-disease classification by ClinGen - https://search.clinicalgenome.org/CCID:006192
Mendeliome v1.1770 SLC52A1 Bryony Thompson Gene: slc52a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1769 SLC52A1 Bryony Thompson Publications for gene: SLC52A1 were set to 29122468; 17689999
Mendeliome v1.1768 SLC52A1 Bryony Thompson reviewed gene: SLC52A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 37510312, 29122468, 21089064; Phenotypes: Maternal riboflavin deficiency MONDO:0014013, Disorders of riboflavin metabolism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1768 BRWD1 Zornitza Stark Tag disputed tag was added to gene: BRWD1.
Mendeliome v1.1768 BRWD1 Zornitza Stark Classified gene: BRWD1 as Red List (low evidence)
Mendeliome v1.1768 BRWD1 Zornitza Stark Gene: brwd1 has been classified as Red List (Low Evidence).
Mendeliome v1.1767 SLC6A20 Bryony Thompson Publications for gene: SLC6A20 were set to 24816252; 19033659
Mendeliome v1.1766 SLC6A20 Bryony Thompson Classified gene: SLC6A20 as Red List (low evidence)
Mendeliome v1.1766 SLC6A20 Bryony Thompson Gene: slc6a20 has been classified as Red List (Low Evidence).
Mendeliome v1.1765 SLC6A20 Bryony Thompson reviewed gene: SLC6A20: Rating: RED; Mode of pathogenicity: None; Publications: 19033659, 36820062, 24816252; Phenotypes: Hyperglycinuria MONDO:0007677; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1765 NFE2L2 Bryony Thompson Tag treatable tag was added to gene: NFE2L2.
Mendeliome v1.1765 BRWD1 Sangavi Sivagnanasundram reviewed gene: BRWD1: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:004289; Phenotypes: primary ciliary dyskinesia MONDO:0016575; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1765 GLUL Zornitza Stark Phenotypes for gene: GLUL were changed from Developmental and epileptic encephalopathy, MONDO:0100062, GLUL-related; Glutamine deficiency, congenital MIM#610015; disorder of amino acid metabolism to Developmental and epileptic encephalopathy 116, MIM# 620806; Glutamine deficiency, congenital MIM#610015; disorder of amino acid metabolism
Mendeliome v1.1764 GLUL Zornitza Stark edited their review of gene: GLUL: Changed phenotypes: Developmental and epileptic encephalopathy 116, MIM# 620806
Mendeliome v1.1764 DAGLA Zornitza Stark Marked gene: DAGLA as ready
Mendeliome v1.1764 DAGLA Zornitza Stark Gene: dagla has been classified as Green List (High Evidence).
Mendeliome v1.1764 DAGLA Zornitza Stark Classified gene: DAGLA as Green List (high evidence)
Mendeliome v1.1764 DAGLA Zornitza Stark Gene: dagla has been classified as Green List (High Evidence).
Mendeliome v1.1763 DAGLA Zornitza Stark gene: DAGLA was added
gene: DAGLA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DAGLA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DAGLA were set to 35737950
Phenotypes for gene: DAGLA were set to Neuroocular syndrome 2, paroxysmal type, MIM# 168885
Review for gene: DAGLA was set to GREEN
Added comment: 9 individuals from 8 families reported with daily paroxysmal spells characterized by eye deviation or nystagmus with abnormal head posturing apparent from birth or early infancy. The episodes tend to be triggered after sleeping, and most patients show improvement of the ocular symptoms over time. Affected individuals also have hypotonia, mild developmental delay, dysarthria, and gait ataxia; most have mildly impaired intellectual development. Seizures are not observed.
Sources: Literature
Mendeliome v1.1762 HOXD12 Zornitza Stark Marked gene: HOXD12 as ready
Mendeliome v1.1762 HOXD12 Zornitza Stark Gene: hoxd12 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1762 HOXD12 Zornitza Stark Classified gene: HOXD12 as Amber List (moderate evidence)
Mendeliome v1.1762 HOXD12 Zornitza Stark Gene: hoxd12 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1761 HOXD12 Zornitza Stark reviewed gene: HOXD12: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Clubfoot (non-syndromic) MONDO:0007342; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1761 PKHD1L1 Zornitza Stark Marked gene: PKHD1L1 as ready
Mendeliome v1.1761 PKHD1L1 Zornitza Stark Gene: pkhd1l1 has been classified as Green List (High Evidence).
Mendeliome v1.1761 PKHD1L1 Zornitza Stark Publications for gene: PKHD1L1 were set to
Mendeliome v1.1760 PKHD1L1 Zornitza Stark Classified gene: PKHD1L1 as Green List (high evidence)
Mendeliome v1.1760 PKHD1L1 Zornitza Stark Gene: pkhd1l1 has been classified as Green List (High Evidence).
Mendeliome v1.1759 EPHX1 Ain Roesley Classified gene: EPHX1 as Green List (high evidence)
Mendeliome v1.1759 EPHX1 Ain Roesley Gene: ephx1 has been classified as Green List (High Evidence).
Mendeliome v1.1758 EPHX1 Lauren Rogers reviewed gene: EPHX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hereditary lipodystrophy, MONDO:0020087, EPHX1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1758 HOXD12 Sangavi Sivagnanasundram gene: HOXD12 was added
gene: HOXD12 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: HOXD12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HOXD12 were set to 38663984
Phenotypes for gene: HOXD12 were set to Clubfoot (non-syndromic) MONDO:0007342
Mode of pathogenicity for gene: HOXD12 was set to Other
Review for gene: HOXD12 was set to GREEN
Added comment: Novel gene-disease association with non-syndromic clubfoot.

10 variants in HOXD12 have been reported in individuals with clubfoot (variants are predominantly missense variants however one rare deletion has been reported).

PMID: 38663984
Around 9 individuals from 4 unrelated families have been reported with clubfoot and the variants were shown to segregate.

N-terminal region and C-terminal homeobox domain of HOXD12 are known to be clusters for pathogenic variants related to clubfoot.
Loss of function variants are less likely to contribute to clubfoot pathogenesis therefore mechanism of disease is suggested as dominant negative but is not confirmed.
Sources: Other
Mendeliome v1.1758 PKHD1L1 Sangavi Sivagnanasundram edited their review of gene: PKHD1L1: Changed publications: 38459354
Mendeliome v1.1758 PKHD1L1 Sangavi Sivagnanasundram gene: PKHD1L1 was added
gene: PKHD1L1 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: PKHD1L1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PKHD1L1 were set to non syndromic hearing loss (MONDO:0020678)
Review for gene: PKHD1L1 was set to GREEN
Added comment: At least 4 individuals from unrelated families with sensorineural hearing loss (SNHL) (2 of the reported probands were from consanguineous parents).
The individuals are either homozygous or compound heterozygous for mutations in PKHD1L1 (missense, frameshift and nonsense mutations have been reported).

In vitro functional assessment as well as a mini-gene assay of Gly605Arg was conducted. The mini-gene assay on Gly605Arg showed that exon skipping occurs resulting in an in-frame deletion of 48 aa. Both studies didn't use a positive control however loss of function or disruption to protein stability is the speculated mechanism of disease.
Sources: Other
Mendeliome v1.1758 RAB32 Bryony Thompson Marked gene: RAB32 as ready
Mendeliome v1.1758 RAB32 Bryony Thompson Gene: rab32 has been classified as Red List (Low Evidence).
Mendeliome v1.1758 RAB32 Bryony Thompson gene: RAB32 was added
gene: RAB32 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB32 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB32 were set to 38614108
Phenotypes for gene: RAB32 were set to Parkinson disease MONDO:0005180
Mode of pathogenicity for gene: RAB32 was set to Other
Review for gene: RAB32 was set to RED
Added comment: A single variant in RAB32 - c.213C>G p.(Ser71Arg) with a significant association with PD (odds ratio [OR] 13.17, 95% CI 2.15-87.23; p=0.0055, 6,043 PD cases and 62,549 controls). The variant cosegregated with autosomal dominant PD in 3 families (9 affected individuals), with incomplete penetrance. In vitro studies demonstrate that RAB32 Ser71Arg activates LRRK2 kinase. The variant is reported as a novel reduced penetrance PD risk factor. The 95% CI for the OR estimate are very wide. A confirmatory study is required for this variant.
Sources: Literature
Mendeliome v1.1757 CYHR1 Zornitza Stark Tag new gene name tag was added to gene: CYHR1.
Mendeliome v1.1757 CCDC91 Bryony Thompson Marked gene: CCDC91 as ready
Mendeliome v1.1757 CCDC91 Bryony Thompson Gene: ccdc91 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1757 CCDC91 Bryony Thompson Classified gene: CCDC91 as Amber List (moderate evidence)
Mendeliome v1.1757 CCDC91 Bryony Thompson Gene: ccdc91 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1756 CCDC91 Bryony Thompson gene: CCDC91 was added
gene: CCDC91 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC91 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCDC91 were set to 38627542
Phenotypes for gene: CCDC91 were set to Punctate palmoplantar keratoderma type III MONDO:0007047
Review for gene: CCDC91 was set to AMBER
Added comment: A single 3-generation Chinese acrokeratoelastoidosis family segregates c.1101 + 1 G > A (causes exon 11 skipping). In vitro knockdown experiments in cell lines demonstrated distended Golgi cisternae, cytoplasmic vesicle accumulation, and lysosome presence. Immnunostaining of si-CCDC91-human skin fibroblasts cells demonstrated tropoelastin accumulation in the Golgi and abnormal extracellular aggregates
Sources: Literature
Mendeliome v1.1755 CYHR1 Bryony Thompson Phenotypes for gene: CYHR1 were changed from Neurodevelopmental disorder and microcephaly, MONDO:0700092, CYHR1-related to Neurodevelopmental disorder, MONDO:0700092, ZTRAF1-related
Mendeliome v1.1754 CYHR1 Bryony Thompson Publications for gene: CYHR1 were set to
Mendeliome v1.1753 CYHR1 Bryony Thompson Classified gene: CYHR1 as Green List (high evidence)
Mendeliome v1.1753 CYHR1 Bryony Thompson Gene: cyhr1 has been classified as Green List (High Evidence).
Mendeliome v1.1752 CYHR1 Bryony Thompson reviewed gene: CYHR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 38641995; Phenotypes: neurodevelopmental disorder MONDO:0700092, ZTRAF1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1752 EHBP1L1 Ain Roesley Phenotypes for gene: EHBP1L1 were changed from non-immune hydrops fetalis MONDO:0009369, EHBP1L1-related to non-immune hydrops fetalis MONDO:0009369, EHBP1L1-related
Mendeliome v1.1751 EHBP1L1 Ain Roesley Phenotypes for gene: EHBP1L1 were changed from Non-immune hydrops fetalis, MONDO:0015193, EHBP1L1-related to non-immune hydrops fetalis MONDO:0009369, EHBP1L1-related
Mendeliome v1.1750 IL27RA Ain Roesley Marked gene: IL27RA as ready
Mendeliome v1.1750 IL27RA Ain Roesley Gene: il27ra has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1750 IL27RA Ain Roesley Classified gene: IL27RA as Amber List (moderate evidence)
Mendeliome v1.1750 IL27RA Ain Roesley Gene: il27ra has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1749 IL27RA Ain Roesley gene: IL27RA was added
gene: IL27RA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IL27RA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL27RA were set to 38509369
Phenotypes for gene: IL27RA were set to Epstein-Barr virus infection MONDO:0005111 , IL27RA-related
Review for gene: IL27RA was set to AMBER
gene: IL27RA was marked as current diagnostic
Added comment: 3 children from 2 families with severe acute EBV infection.

fam1: homozygous for p.(Gln96*) (NMD-pred)
fam2: chet for p.(Arg446Gly) and c.1142-2A>C

the splice variant in fam2 was found to to result in an in-frame deletion p.(Gln381_Ala395del)
the missense in fam2 is hypothesised to be a hypomorphic allele:
- out of 15 Homs in the Finnish database, 2 had hospital diagnoses of EBV IM
- expression of this variant on its own results in a weak but detectable IL-27RA expression associated with significant increase in STAT1/3 phosphorus in response to IL-27 stimulation

borderline amber/green due to functional studies performed
Sources: Literature
Mendeliome v1.1748 SHH Ain Roesley Publications for gene: SHH were set to 21976454; 12503095; 22791840; 19057928; 19533790; 38562108; 29321670, 32703609
Mendeliome v1.1747 SHH Ain Roesley edited their review of gene: SHH: Changed publications: 38562108, 29321670, 32703609
Mendeliome v1.1747 SHH Ain Roesley Publications for gene: SHH were set to 21976454; 12503095; 22791840; 19057928; 19533790,38562108, 29321670, 32703609
Mendeliome v1.1746 SHH Ain Roesley Phenotypes for gene: SHH were changed from Holoprosencephaly 3, MIM#142945; Microphthalmia with coloboma 5, MIM#611638; Single median maxillary central incisor, MIM#147250 to Holoprosencephaly 3, MIM#142945; Microphthalmia with coloboma 5, MIM#611638; Single median maxillary central incisor, MIM#147250; Hypertelorism, ACC, intellectual disability
Mendeliome v1.1745 SHH Ain Roesley Publications for gene: SHH were set to 21976454; 12503095; 22791840; 19057928; 19533790
Mendeliome v1.1744 SHH Ain Roesley reviewed gene: SHH: Rating: GREEN; Mode of pathogenicity: None; Publications: 38562108, 29321670, 32703609; Phenotypes: Hypertelorism, ACC, intellectual disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1744 PRMT9 Zornitza Stark Marked gene: PRMT9 as ready
Mendeliome v1.1744 PRMT9 Zornitza Stark Gene: prmt9 has been classified as Red List (Low Evidence).
Mendeliome v1.1744 PRMT9 Zornitza Stark Phenotypes for gene: PRMT9 were changed from Neurodevelopmental disorder, MONDO:0100500 to Neurodevelopmental disorder, MONDO:0100500, PRMT9-related
Mendeliome v1.1743 SUPT7L Zornitza Stark Marked gene: SUPT7L as ready
Mendeliome v1.1743 SUPT7L Zornitza Stark Gene: supt7l has been classified as Red List (Low Evidence).
Mendeliome v1.1743 SUPT7L Zornitza Stark Phenotypes for gene: SUPT7L were changed from Lipodystrophy, MONDO:0006573 to Lipodystrophy, MONDO:0006573, SUPT7L-related
Mendeliome v1.1742 PQLC2 Zornitza Stark Marked gene: PQLC2 as ready
Mendeliome v1.1742 PQLC2 Zornitza Stark Gene: pqlc2 has been classified as Green List (High Evidence).
Mendeliome v1.1742 PQLC2 Zornitza Stark Phenotypes for gene: PQLC2 were changed from Retinitis pigmentosa, MONDO:0019200 to Retinitis pigmentosa, MONDO:0019200, PQLC2-related
Mendeliome v1.1741 PQLC2 Zornitza Stark Publications for gene: PQLC2 were set to PMID: 35486108; and online publication GiM Feb 2024
Mendeliome v1.1740 PQLC2 Zornitza Stark Tag new gene name tag was added to gene: PQLC2.
Mendeliome v1.1740 SLC39A12 Zornitza Stark Marked gene: SLC39A12 as ready
Mendeliome v1.1740 SLC39A12 Zornitza Stark Gene: slc39a12 has been classified as Red List (Low Evidence).
Mendeliome v1.1740 SLC39A12 Zornitza Stark Phenotypes for gene: SLC39A12 were changed from Retinitis pigmentosa, MONDO:0019200 to Retinitis pigmentosa, MONDO:0019200, SLC39A12-related
Mendeliome v1.1739 SLC4A7 Zornitza Stark Marked gene: SLC4A7 as ready
Mendeliome v1.1739 SLC4A7 Zornitza Stark Gene: slc4a7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1739 SLC4A7 Zornitza Stark Phenotypes for gene: SLC4A7 were changed from Retinitis pigmentosa, MONDO:0019200 to Retinitis pigmentosa, MONDO:0019200, SLC4A7-related
Mendeliome v1.1738 SLC4A7 Chirag Patel Classified gene: SLC4A7 as Amber List (moderate evidence)
Mendeliome v1.1738 SLC4A7 Chirag Patel Gene: slc4a7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1737 SLC4A7 Chirag Patel gene: SLC4A7 was added
gene: SLC4A7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC4A7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC4A7 were set to PMID: 35486108, 32594822
Phenotypes for gene: SLC4A7 were set to Retinitis pigmentosa, MONDO:0019200
Review for gene: SLC4A7 was set to AMBER
Added comment: Total 4 individuals from 3 families (2 known to be from same ethnic origin: Oriental-Jewish) with adult onset retinitis pigmentosa. All individuals had same homozygous frameshift variant in SLC4A7 gene (p.P670Sfs*6). RNA seq analysis revealed retinal expression in human and mouse samples. Immunohistochemistry of human and mouse retina revealed relatively strong expression in various retinal layers. Western blot analysis in fibroblasts from 1 patient showed absence of encoded protein.
Sources: Literature
Mendeliome v1.1736 SLC39A12 Chirag Patel gene: SLC39A12 was added
gene: SLC39A12 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC39A12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC39A12 were set to PMID: 35486108
Phenotypes for gene: SLC39A12 were set to Retinitis pigmentosa, MONDO:0019200
Review for gene: SLC39A12 was set to RED
Added comment: WES (with targeted analysis of SLC genes) in 913 cases from 785 families with inherited retinal dystrophy. They identified 1 homozygous variant in SLC39A12 in 1 individual with adult-onset mild widespread retinal degeneration with marked macular involvement. No functional data. RNA seq analysis revealed retinal expression in human samples. Immunohistochemistry of human and mouse retina revealed comprehensive expression in various retinal cells including retinal pigment epithelium.
Sources: Literature
Mendeliome v1.1735 PQLC2 Chirag Patel Classified gene: PQLC2 as Green List (high evidence)
Mendeliome v1.1735 PQLC2 Chirag Patel Gene: pqlc2 has been classified as Green List (High Evidence).
Mendeliome v1.1734 PQLC2 Chirag Patel gene: PQLC2 was added
gene: PQLC2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PQLC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PQLC2 were set to PMID: 35486108; and online publication GiM Feb 2024
Phenotypes for gene: PQLC2 were set to Retinitis pigmentosa, MONDO:0019200
Review for gene: PQLC2 was set to GREEN
gene: PQLC2 was marked as current diagnostic
Added comment: HGNC Gene Symbol: SLC66A1
Total 8 individuals from 6 families.

Millo et al. (2022)(PMID: 35486108) -
WES (with targeted analysis of SLC genes) in 913 cases from 785 families with inherited retinal dystrophy. They identified 2 different homozygous variants in SLC66A1 in 3 individuals from 2 families with adult-onset retinal dystrophy. No functional data.


Olinger et al. (2024)(https://www.sciencedirect.com/science/article/pii/S2949774424009804) -
CNV analysis of trio and non-trio WGS data from Genomics England 100K genomes project. They identified homozygous 21kb deletion spanning nearly entire SLC66A1 gene in 2 siblings with adult-onset rod-cone dystrophy (parents HTZ carriers). Review of cohort data then identified homozygous LOF variants (1 nonsense, 2 frameshift) in another 3 individuals with rod-cone dystrophy.
Sources: Literature
Mendeliome v1.1733 SUPT7L Chirag Patel gene: SUPT7L was added
gene: SUPT7L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SUPT7L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SUPT7L were set to PMID: 38592547
Phenotypes for gene: SUPT7L were set to Lipodystrophy, MONDO:0006573
Review for gene: SUPT7L was set to RED
Added comment: 1 case with generalised lipodystrophy, growth retardation, congenital cataracts, severe developmental delay and progeriod features. Trio WGS identified compound heterozygous variants in SUPT7L (missense causing abnormal splicing + frameshift). Variants validated with Sanger. SUPT7L encodes a component of the core structural module of the STAGA complex - a nuclear multifunctional protein complex that plays a role in various cellular processes (e.g. transcription factor binding, protein acetylation, splicing, and DNA damage control). Immunolabelling in fibroblasts from patient showed complete absence of SUPT7L protein. Transcriptome data from individual revealed downregulation of several gene sets associated with DNA replication, DNA repair, cell cycle, and transcription.
Sources: Literature
Mendeliome v1.1732 PRMT9 Chirag Patel gene: PRMT9 was added
gene: PRMT9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRMT9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRMT9 were set to PMID: 38561334
Phenotypes for gene: PRMT9 were set to Neurodevelopmental disorder, MONDO:0100500
Review for gene: PRMT9 was set to RED
Added comment: A homozygous variant (G189R) in PRMT9 is reported based on large WGS study in 136 consanguineous families - unclear if only found in 1 family and no clinical information on case(s).

PMRTs (protein arginine methyltransferases) catalyse post translational modification via arginine methylation. Functional studies showed that the G189R variant abolishes PRMT9's methyltransferase activity - specifically at the R508 residue of SF3B2 RNA (exclusively methylated by PRMT9) - and leads to heavy PRMT9 ubiquitination, and abnormal splicing activity of SF3B2. Knock out mouse model showed PRMT9 loss in excitatory neurons leads to aberrant synapse development and impaired learning and memory.
Sources: Literature
Mendeliome v1.1731 JAK1 Zornitza Stark Phenotypes for gene: JAK1 were changed from Eosinophilia; Eosinophilic enteritis; Thyroid disease; Poor growth; Viral infections; Susceptibility to mycobacteria and viruses to Autoinflammation, immunde dysregulation, and eosinophilia, MIM# 618999; Eosinophilia; Eosinophilic enteritis; Thyroid disease; Poor growth; Viral infections; Susceptibility to mycobacteria and viruses
Mendeliome v1.1730 JAK1 Zornitza Stark Publications for gene: JAK1 were set to 28111307; 28008925; 30671064
Mendeliome v1.1729 JAK1 Zornitza Stark Classified gene: JAK1 as Green List (high evidence)
Mendeliome v1.1729 JAK1 Zornitza Stark Gene: jak1 has been classified as Green List (High Evidence).
Mendeliome v1.1728 JAK1 Zornitza Stark edited their review of gene: JAK1: Added comment: PMID 38563820: 59 individuals presenting with autoimmunity, atopy, colitis, and/or dermatitis and one of four JAK1 variants.; Changed rating: GREEN; Changed publications: 28111307, 28008925, 30671064, 38563820; Changed phenotypes: Autoinflammatory syndrome, MONDO:0019751, JAK1-related, Eosinophilia, Eosinophilic enteritis, Thyroid disease, Poor growth, Viral infections, Susceptibility to mycobacteria and viruses, Autoinflammation, immunde dysregulation, and eosinophilia, MIM# 618999
Mendeliome v1.1728 SRPK3 Zornitza Stark Marked gene: SRPK3 as ready
Mendeliome v1.1728 SRPK3 Zornitza Stark Gene: srpk3 has been classified as Green List (High Evidence).
Mendeliome v1.1728 SRPK3 Zornitza Stark Classified gene: SRPK3 as Green List (high evidence)
Mendeliome v1.1728 SRPK3 Zornitza Stark Gene: srpk3 has been classified as Green List (High Evidence).
Mendeliome v1.1727 SRPK3 Zornitza Stark gene: SRPK3 was added
gene: SRPK3 was added to Mendeliome. Sources: Literature
digenic tags were added to gene: SRPK3.
Mode of inheritance for gene: SRPK3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SRPK3 were set to 38429495
Phenotypes for gene: SRPK3 were set to Myopathy, MONDO:0005336, digenic SRPK3- and TTN-related
Review for gene: SRPK3 was set to GREEN
Added comment: 33 individuals reported with SRPK3 variants but myopathy only occurred when TTN variant also present (most truncating). Zebrafish model supports digenic model of inheritance.
Sources: Literature
Mendeliome v1.1726 OTULIN Zornitza Stark Publications for gene: OTULIN were set to 27523608; 27559085; 35587511
Mendeliome v1.1725 OTULIN Zornitza Stark edited their review of gene: OTULIN: Added comment: Three individuals reported with de novo missense variants and auto inflammatory syndrome. Two had at the same variant, p.Cys129Ser. Experimental data supports dominant negative mechanism. Fourth individual with heterozygous variant in PMID 38129331 and severe fasciitis.; Changed publications: 27523608, 27559085, 35587511, 38630025, 38652464, 38129331
Mendeliome v1.1725 SHARPIN Zornitza Stark Phenotypes for gene: SHARPIN were changed from Autoinflammatory syndrome, MONDO:0019751, SHARPIN-related to Autoinflammation with episodic fever and immune dysregulation, MIM# 620795
Mendeliome v1.1724 SHARPIN Zornitza Stark edited their review of gene: SHARPIN: Changed phenotypes: Autoinflammation with episodic fever and immune dysregulation, MIM# 620795
Mendeliome v1.1724 OTUD7A Zornitza Stark Phenotypes for gene: OTUD7A were changed from Intellectual disability; Epilepsy to Neurodevelopmental disorder with hypotonia and seizures, MIM# 620790
Mendeliome v1.1723 OTUD7A Zornitza Stark edited their review of gene: OTUD7A: Changed phenotypes: Neurodevelopmental disorder with hypotonia and seizures, MIM# 620790
Mendeliome v1.1723 AMPD2 Bryony Thompson Deleted their review
Mendeliome v1.1723 AMPD2 Bryony Thompson commented on gene: AMPD2
Mendeliome v1.1723 AMPD2 Bryony Thompson Deleted their review
Mendeliome v1.1723 SAR1B Bryony Thompson Deleted their review
Mendeliome v1.1723 SAR1B Bryony Thompson commented on gene: SAR1B
Mendeliome v1.1723 SAR1B Bryony Thompson Deleted their review
Mendeliome v1.1723 KIAA1024L Zornitza Stark Tag new gene name tag was added to gene: KIAA1024L.
Mendeliome v1.1723 KIAA1024L Zornitza Stark Marked gene: KIAA1024L as ready
Mendeliome v1.1723 KIAA1024L Zornitza Stark Gene: kiaa1024l has been classified as Green List (High Evidence).
Mendeliome v1.1723 KIAA1024L Zornitza Stark Classified gene: KIAA1024L as Green List (high evidence)
Mendeliome v1.1723 KIAA1024L Zornitza Stark Gene: kiaa1024l has been classified as Green List (High Evidence).
Mendeliome v1.1722 EHBP1L1 Zornitza Stark Phenotypes for gene: EHBP1L1 were changed from Non-immune hydrops fetalis, MONDO:0015193, EHBP1l1-related to Non-immune hydrops fetalis, MONDO:0015193, EHBP1L1-related
Mendeliome v1.1721 EHBP1L1 Zornitza Stark Classified gene: EHBP1L1 as Green List (high evidence)
Mendeliome v1.1721 EHBP1L1 Zornitza Stark Gene: ehbp1l1 has been classified as Green List (High Evidence).
Mendeliome v1.1720 EHBP1L1 Zornitza Stark reviewed gene: EHBP1L1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Non-immune hydrops fetalis, MONDO:0015193, EHBP1L1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1720 PSMB9 Zornitza Stark Phenotypes for gene: PSMB9 were changed from Proteasome-associated autoinflammatory syndrome 3, digenic, MIM# 617591 to Proteasome-associated autoinflammatory syndrome 3, digenic, MIM# 617591; Proteasome-associated autoinflammatory syndrome 6, MIM# 620796
Mendeliome v1.1719 PSMB9 Zornitza Stark edited their review of gene: PSMB9: Changed phenotypes: Proteasome-associated autoinflammatory syndrome 3, digenic, MIM# 617591, Proteasome-associated autoinflammatory syndrome 6, MIM# 620796
Mendeliome v1.1719 PACSIN3 Zornitza Stark Marked gene: PACSIN3 as ready
Mendeliome v1.1719 PACSIN3 Zornitza Stark Gene: pacsin3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1719 PACSIN3 Zornitza Stark Classified gene: PACSIN3 as Amber List (moderate evidence)
Mendeliome v1.1719 PACSIN3 Zornitza Stark Gene: pacsin3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1718 PACSIN3 Zornitza Stark gene: PACSIN3 was added
gene: PACSIN3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PACSIN3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PACSIN3 were set to 38637313
Phenotypes for gene: PACSIN3 were set to Myopathy, MONDO:0005336, PACSIN3-related
Review for gene: PACSIN3 was set to AMBER
Added comment: Two unrelated families with LoF variants, one homozygous. Muscle phenotype including raised CK. Supportive mouse model.
Sources: Literature
Mendeliome v1.1717 RNU4-2 Zornitza Stark changed review comment from: Emerging evidence that de novo variants in this gene cause ID.
Sources: Literature; to: Over 100 individuals with ID found to have de novo variants in this gene. Please note difficult to identify on ES.
Sources: Literature
Mendeliome v1.1717 RNU4-2 Zornitza Stark Publications for gene: RNU4-2 were set to
Mendeliome v1.1716 RNU4-2 Zornitza Stark edited their review of gene: RNU4-2: Changed publications: 38645094
Mendeliome v1.1716 FOSL2 Zornitza Stark Phenotypes for gene: FOSL2 were changed from Neurodevelopmental disorder, MONDO:0700092, FOSL2-related to Aplasia cutis-enamel dysplasia syndrome, MIM# 620789
Mendeliome v1.1715 FOSL2 Zornitza Stark reviewed gene: FOSL2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Aplasia cutis-enamel dysplasia syndrome, MIM# 620789; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1715 KIAA1024L Achchuthan Shanmugasundram gene: KIAA1024L was added
gene: KIAA1024L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KIAA1024L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA1024L were set to 35727972
Phenotypes for gene: KIAA1024L were set to Deafness, autosomal recessive 120, OMIM:620238
Review for gene: KIAA1024L was set to GREEN
Added comment: New gene name - MINAR2

PMID:35727972 reported 13 patients from four unrelated families with non-syndromic sensorineural hearing loss. Four of these patients had prelingual onset of severe to profound, progressive bilateral hearing loss. The other nine patients had congenital onset of severe to profound bilateral hearing loss, which was not progressive on one patient, while data was not available for the other.

Three different homozygous variants (c.144G > A/ p.Trp48Ter, c.412_419delCGGTTTTG/ p.Arg138Valfs*10 and c.393G > T/ p.Lys131Asn) were identified in MINAR2/ KIAA1024L gene in these patients.

There is some functional evidence available for the p.Lys131Asn variant. In addition, mice with loss of function of the Minar2 protein present with rapidly progressive sensorineural hearing loss.

This gene has also been associated with relevant phenotype in OMIM (MIM #620238).
Sources: Literature
Mendeliome v1.1715 CYLD Zornitza Stark Classified gene: CYLD as Green List (high evidence)
Mendeliome v1.1715 CYLD Zornitza Stark Gene: cyld has been classified as Green List (High Evidence).
Mendeliome v1.1714 CYLD Zornitza Stark Classified gene: CYLD as Amber List (moderate evidence)
Mendeliome v1.1714 CYLD Zornitza Stark Gene: cyld has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1713 CYLD Zornitza Stark commented on gene: CYLD: DEFINITIVE by ClinGen for the cutaneous disorder, Brooke-Spiegler syndrome, 605041.
LIMITED for FTD/ALS -- rated as Amber due to multiple affected individuals and experimental data.
Mendeliome v1.1713 MARS Zornitza Stark Mode of inheritance for gene: MARS was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1712 MARS Zornitza Stark edited their review of gene: MARS: Added comment: The mono-allelic gene-disease associations have LIMITED evidence.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1712 PMP2 Zornitza Stark Mode of pathogenicity for gene: PMP2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v1.1711 PMP2 Zornitza Stark Classified gene: PMP2 as Amber List (moderate evidence)
Mendeliome v1.1711 PMP2 Zornitza Stark Gene: pmp2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1710 PMP2 Zornitza Stark reviewed gene: PMP2: Rating: AMBER; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 26257172, 27009151, 30249361, 31412900, 26828946, 32277537; Phenotypes: Charcot-Marie-Tooth disease, demyelinating, type 1G, 618279; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1710 ELANE Zornitza Stark Publications for gene: ELANE were set to 19036076
Mendeliome v1.1709 ELANE Zornitza Stark Mode of pathogenicity for gene: ELANE was changed from Other to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v1.1708 ELANE Zornitza Stark edited their review of gene: ELANE: Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mendeliome v1.1708 CNOT1 Zornitza Stark commented on gene: CNOT1: DEFINITIVE by ClinGen for Neurodevelopmental disorder.
Mendeliome v1.1708 SHARPIN Zornitza Stark Marked gene: SHARPIN as ready
Mendeliome v1.1708 SHARPIN Zornitza Stark Gene: sharpin has been classified as Green List (High Evidence).
Mendeliome v1.1708 SHARPIN Zornitza Stark Classified gene: SHARPIN as Green List (high evidence)
Mendeliome v1.1708 SHARPIN Zornitza Stark Gene: sharpin has been classified as Green List (High Evidence).
Mendeliome v1.1707 SHARPIN Zornitza Stark gene: SHARPIN was added
gene: SHARPIN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SHARPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHARPIN were set to 38609546
Phenotypes for gene: SHARPIN were set to Autoinflammatory syndrome, MONDO:0019751, SHARPIN-related
Review for gene: SHARPIN was set to GREEN
Added comment: Two unrelated patients with homozygous frameshift variants presenting with: P1 - recurrent fever, parotitis, joint inflammation, colitis and chronic otitis media necessitating tympanoplasty P2 - recurrent fever episodes with lymphadenopathy and vomiting every 2–3 weeks. Extensive functional data and mouse model.
Sources: Literature
Mendeliome v1.1706 RTN2 Zornitza Stark Phenotypes for gene: RTN2 were changed from Spastic paraplegia 12, autosomal dominant, 604805; MONDO:0011489 to Spastic paraplegia 12, autosomal dominant, 604805; MONDO:0011489; distal hereditary motor neuropathy, MONDO:0018894
Mendeliome v1.1705 RTN2 Zornitza Stark Publications for gene: RTN2 were set to 22232211; 27165006
Mendeliome v1.1704 RTN2 Zornitza Stark Mode of inheritance for gene: RTN2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1703 PTCRA Zornitza Stark Marked gene: PTCRA as ready
Mendeliome v1.1703 PTCRA Zornitza Stark Gene: ptcra has been classified as Green List (High Evidence).
Mendeliome v1.1703 PTCRA Zornitza Stark Phenotypes for gene: PTCRA were changed from Autoimmunity, HP:0002960; lymphopenia, MONDO:0003783 to Autoinflammatory syndrome, MONDO:0019751, PTCRA-related
Mendeliome v1.1702 PTCRA Zornitza Stark Classified gene: PTCRA as Green List (high evidence)
Mendeliome v1.1702 PTCRA Zornitza Stark Gene: ptcra has been classified as Green List (High Evidence).
Mendeliome v1.1701 PTCRA Zornitza Stark reviewed gene: PTCRA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammatory syndrome, MONDO:0019751, PTCRA-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1701 SLC37A3 Zornitza Stark Marked gene: SLC37A3 as ready
Mendeliome v1.1701 SLC37A3 Zornitza Stark Gene: slc37a3 has been classified as Green List (High Evidence).
Mendeliome v1.1701 SLC37A3 Zornitza Stark Classified gene: SLC37A3 as Green List (high evidence)
Mendeliome v1.1701 SLC37A3 Zornitza Stark Gene: slc37a3 has been classified as Green List (High Evidence).
Mendeliome v1.1700 CADM3 Zornitza Stark Publications for gene: CADM3 were set to PMID: 33889941
Mendeliome v1.1699 CADM3 Zornitza Stark Classified gene: CADM3 as Green List (high evidence)
Mendeliome v1.1699 CADM3 Zornitza Stark Gene: cadm3 has been classified as Green List (High Evidence).
Mendeliome v1.1698 CADM3 Zornitza Stark edited their review of gene: CADM3: Added comment: Two additional families reported with a different variant, de novo in one family.; Changed rating: GREEN; Changed publications: 38074074
Mendeliome v1.1698 EMILIN1 Chern Lim reviewed gene: EMILIN1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuronopathy, distal hereditary motor, autosomal dominant 10, MIM#620080, Aortic aneurysm, MONDO:0005160, EMILIN1-related, AR.; Mode of inheritance: None
Mendeliome v1.1698 ACBD6 Zornitza Stark Phenotypes for gene: ACBD6 were changed from Neurodevelopmental disorder (MONDO#0700092), ACBD6-related to Neurodevelopmental disorder with progressive movement abnormalities, MIM# 620785
Mendeliome v1.1697 ACBD6 Zornitza Stark reviewed gene: ACBD6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with progressive movement abnormalities, MIM# 620785; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1697 IQSEC2 Ain Roesley Phenotypes for gene: IQSEC2 were changed from Mental retardation, X-linked 1/78, MIM# 309530, MONDO:0010656; Severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome MONDO:0018347 to Intellectual developmental disorder, X-linked 1 MIM#309530, MONDO:0010656; Severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome MONDO:0018347
Mendeliome v1.1696 SLC37A3 Achchuthan Shanmugasundram gene: SLC37A3 was added
gene: SLC37A3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC37A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC37A3 were set to 28041643; 35486108
Phenotypes for gene: SLC37A3 were set to retinitis pigmentosa, MONDO:0019200
Review for gene: SLC37A3 was set to GREEN
Added comment: Three unrelated cases reported with biallelic variants in SLC37A3 gene (One case in PMID:28041643 and two cases in PMID:35486108) and with autosomal recessive retinitis pigmentosa.
Sources: Literature
Mendeliome v1.1696 PTCRA Achchuthan Shanmugasundram gene: PTCRA was added
gene: PTCRA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTCRA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTCRA were set to 38422122
Phenotypes for gene: PTCRA were set to Autoimmunity, HP:0002960; lymphopenia, MONDO:0003783
Review for gene: PTCRA was set to GREEN
Added comment: PMID:38422122 reported the identification of 10 individuals from seven kindreds from four different ethnicities with biallelic PTCRA variants (homozygous in five kindreds and compound heterozygous in two kindreds).

Six of these 10 patients were clinically asymptomatic at their most recent evaluation, while other four patients displayed infection, lymphoproliferation, and/or autoimmunity with an onset during their teens or in adulthood. One of these patients died from SARS-CoV-2 pneumonia at the age of 24 years. Patient 9 had a small thymus on MRI at the age of 2 years, whereas P5 and P6 had no visible thymus at the ages of 13 and 8 years, respectively. Three of the nine patients with pLOF PTCRA variants tested were found to produce autoantibodies, several of which were associated with clinical manifestations. Anti-thyroid autoantibodies and/or clinically overt thyroiditis were found in three of the nine patients. P7, who suffered from recurrent herpes infections, had autoantibodies against type I interferons.

Two of those identified variants are hypomorphic and are associated with autoimmunity. In addition, there is extensive functional and epidemiological data available.
Sources: Literature
Mendeliome v1.1696 NAA60 Zornitza Stark Phenotypes for gene: NAA60 were changed from Basal ganglia calcification, MONDO:0008947, NAA60-related to Basal ganglia calcification, idiopathic, 9, autosomal recessive, MIM# 620786
Mendeliome v1.1695 NAA60 Zornitza Stark reviewed gene: NAA60: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Basal ganglia calcification, idiopathic, 9, autosomal recessive, MIM# 620786; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1695 RTN2 Achchuthan Shanmugasundram changed review comment from: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

All affected individuals exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography.

Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences.

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.; to: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

All affected individuals exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography.

Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain, and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences.

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.
Mendeliome v1.1695 RTN2 Achchuthan Shanmugasundram changed review comment from: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography.

Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences.

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.; to: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

All affected individuals exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography.

Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences.

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.
Mendeliome v1.1695 RTN2 Achchuthan Shanmugasundram reviewed gene: RTN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38527963; Phenotypes: distal hereditary motor neuropathy, MONDO:0018894; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1695 FAM58A Zornitza Stark Mode of inheritance for gene: FAM58A was changed from Other to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v1.1694 FAM58A Zornitza Stark reviewed gene: FAM58A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v1.1694 TUBA8 Sangavi Sivagnanasundram reviewed gene: TUBA8: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:006476; Phenotypes: polymicrogyria with optic nerve hypoplasia (MONDO:0013172); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1694 KIF1BP Sangavi Sivagnanasundram reviewed gene: KIF1BP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.1694 SNF8 Zornitza Stark Phenotypes for gene: SNF8 were changed from Developmental and epileptic encephalopathy 115, MIM#620783 to Developmental and epileptic encephalopathy 115, MIM#620783; Neurodevelopmental disorder plus optic atrophy, MIM# 620784
Mendeliome v1.1693 SNF8 Zornitza Stark edited their review of gene: SNF8: Added comment: Four individuals from 3 families with NDD plus OA, rather than DEE.; Changed phenotypes: Developmental and epileptic encephalopathy 115, MIM#620783, Neurodevelopmental disorder plus optic atrophy, MIM# 620784
Mendeliome v1.1693 NSUN6 Zornitza Stark Phenotypes for gene: NSUN6 were changed from neurodevelopmental disorder MONDO:0700092, NSUN6-related to Intellectual developmental disorder, autosomal recessive 82, MIM# 620779
Mendeliome v1.1692 NSUN6 Zornitza Stark reviewed gene: NSUN6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal recessive 82, MIM# 620779; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1692 CANVAS_ACAGG Bryony Thompson Classified STR: CANVAS_ACAGG as Green List (high evidence)
Mendeliome v1.1692 CANVAS_ACAGG Bryony Thompson Str: canvas_acagg has been classified as Green List (High Evidence).
Mendeliome v1.1691 CANVAS_ACAGG Bryony Thompson edited their review of STR: CANVAS_ACAGG: Added comment: Additional 4 unrelated cases homozygous for the (ACAGG)exp and one compound het with AAGGG/ACAGG expansion in a Japanese neuropathy cohort.; Changed rating: GREEN; Changed publications: 33103729, 36061987; Changed phenotypes: cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome MONDO:0044720; Set clinically relevant: yes
Mendeliome v1.1691 CAPRIN1 Zornitza Stark Phenotypes for gene: CAPRIN1 were changed from Neurodevelopmental disorder, CAPRIN1-related MONDO:0700092; Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, MIM# 620636 to Neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder, MIM# 620782; Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, MIM# 620636
Mendeliome v1.1690 KDM5C Ain Roesley Phenotypes for gene: KDM5C were changed from Mental retardation, X-linked, syndromic, Claes-Jensen type, MIM# 300534; MONDO:0010355 to Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type MIM# 300534; MONDO:0010355
Mendeliome v1.1689 PSMA5 Zornitza Stark Marked gene: PSMA5 as ready
Mendeliome v1.1689 PSMA5 Zornitza Stark Gene: psma5 has been classified as Red List (Low Evidence).
Mendeliome v1.1689 PSMA5 Zornitza Stark gene: PSMA5 was added
gene: PSMA5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PSMA5 was set to Other
Publications for gene: PSMA5 were set to 37600812
Phenotypes for gene: PSMA5 were set to Inborn error of immunity, MONDO:0003778, PSMA5-related; PRAAS/CANDLE
Review for gene: PSMA5 was set to RED
Added comment: Single patient with heterozygous PSMB8 variant and de-novo PSMA5 truncating variant (p.Arg168*) with clinical features of CANDLE. Patient also had splice site variant in PSMC5. In silico modelling showing interaction of PSMB8 and PSMA5. PSMA5/a5 is a constitutive component of the 20S core proteasome, ? digenic model of disease.
Sources: Literature
Mendeliome v1.1688 SNF8 Zornitza Stark Phenotypes for gene: SNF8 were changed from Neurodevelopmental disorder (MONDO:0700092), SNF8-related to Developmental and epileptic encephalopathy 115, MIM#620783
Mendeliome v1.1687 SNF8 Zornitza Stark reviewed gene: SNF8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy 115, MIM#620783; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1687 CNOT1 Sangavi Sivagnanasundram reviewed gene: CNOT1: Rating: AMBER; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:004485; Phenotypes: holoprosencephaly 12 with or without pancreatic agenesis MONDO:0032787; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1687 CENPE Sangavi Sivagnanasundram reviewed gene: CENPE: Rating: RED; Mode of pathogenicity: None; Publications: https://search.clinicalgenome.org/CCID:004413; Phenotypes: autosomal recessive primary microcephaly MONDO:0016660; Mode of inheritance: None
Mendeliome v1.1687 PURA Ain Roesley Phenotypes for gene: PURA were changed from Mental retardation, autosomal dominant 31, MIM# 616158 to Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (OMIM 616158)
Mendeliome v1.1686 EFEMP1 Zornitza Stark Phenotypes for gene: EFEMP1 were changed from Glaucoma 1, open angle, H, MIM# 611276; Doyne honeycomb degeneration of retina, MIM# 126600; EFEMP1-related connective tissue disorder to Doyne honeycomb degeneration of retina, MIM# 126600; Cutis laxa, autosomal recessive, type ID, MIM# 620780; Glaucoma 1, open angle, H, MIM# 611276
Mendeliome v1.1685 EFEMP1 Zornitza Stark edited their review of gene: EFEMP1: Changed phenotypes: Doyne honeycomb degeneration of retina, MIM# 126600, Cutis laxa, autosomal recessive, type ID, MIM# 620780, Glaucoma 1, open angle, H, MIM# 611276
Mendeliome v1.1685 GALE Zornitza Stark Phenotypes for gene: GALE were changed from Galactose epimerase deficiency MIM#230350; Disorders of galactose metabolism to Galactose epimerase deficiency MIM#230350; Thrombocytopenia 12, syndromic, MIM#620776
Mendeliome v1.1684 GALE Zornitza Stark Publications for gene: GALE were set to 27604308; 9700591
Mendeliome v1.1683 GALE Zornitza Stark reviewed gene: GALE: Rating: GREEN; Mode of pathogenicity: None; Publications: 30247636, 34159722, 36395340; Phenotypes: Thrombocytopenia 12, syndromic, MIM#620776; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1683 BANF1 Zornitza Stark Phenotypes for gene: BANF1 were changed from Nestor-Guillermo progeria syndrome, MIM# 614008 to Nestor-Guillermo progeria syndrome, MIM# 614008; Neurodevelopmental disorder, MONDO:0700092, BANF1-related; Hereditary peripheral neuropathy, MONDO:0020127, BANF1-related
Mendeliome v1.1682 BANF1 Zornitza Stark Publications for gene: BANF1 were set to 32783369; 21549337
Mendeliome v1.1681 BANF1 Zornitza Stark Mode of inheritance for gene: BANF1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1680 BANF1 Zornitza Stark changed review comment from: Two Spanish families reported but likely founder effect. One additional family. Lipoatrophy reported.; to: Bi-allelic disease: Two Spanish families reported with progeria but likely founder effect. One additional family. Lipoatrophy reported.
Mendeliome v1.1680 BANF1 Zornitza Stark edited their review of gene: BANF1: Added comment: PMID 35982159: Single individual reported with a de novo variant, p.Ala87Thr, and a neurodevelopmental disorder.

PMID 36980188: Hereditary peripheral neuropathy, MONDO:0020127, BANF1-related; Changed publications: 32783369, 21549337, 35982159, 36980188; Changed phenotypes: Nestor-Guillermo progeria syndrome, MIM# 614008, Neurodevelopmental disorder, MONDO:0700092, BANF1-related, Hereditary peripheral neuropathy, MONDO:0020127, BANF1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1680 FILIP1 Zornitza Stark Phenotypes for gene: FILIP1 were changed from Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related to Neuromuscular disorder, congenital, with dysmorphic facies, MIM# 620775
Mendeliome v1.1679 FILIP1 Zornitza Stark reviewed gene: FILIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuromuscular disorder, congenital, with dysmorphic facies, MIM# 620775; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1679 RNU4-2 Zornitza Stark Marked gene: RNU4-2 as ready
Mendeliome v1.1679 RNU4-2 Zornitza Stark Gene: rnu4-2 has been classified as Green List (High Evidence).
Mendeliome v1.1679 RNU4-2 Zornitza Stark Classified gene: RNU4-2 as Green List (high evidence)
Mendeliome v1.1679 RNU4-2 Zornitza Stark Gene: rnu4-2 has been classified as Green List (High Evidence).
Mendeliome v1.1678 RNU4-2 Zornitza Stark gene: RNU4-2 was added
gene: RNU4-2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNU4-2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RNU4-2 were set to Neurodevelopmental disorder, MONDO:0700092, RNU4-2 related
Review for gene: RNU4-2 was set to GREEN
Added comment: Emerging evidence that de novo variants in this gene cause ID.
Sources: Literature
Mendeliome v1.1677 YKT6 Zornitza Stark Marked gene: YKT6 as ready
Mendeliome v1.1677 YKT6 Zornitza Stark Gene: ykt6 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1677 YKT6 Zornitza Stark Classified gene: YKT6 as Amber List (moderate evidence)
Mendeliome v1.1677 YKT6 Zornitza Stark Gene: ykt6 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1676 YKT6 Zornitza Stark gene: YKT6 was added
gene: YKT6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: YKT6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YKT6 were set to 38522068
Phenotypes for gene: YKT6 were set to Syndromic disease, MONDO:0002254, YKT6-related
Review for gene: YKT6 was set to AMBER
Added comment: Two individuals homozygous for YKT6 [NM_006555.3:c.554A>G p.(Tyr185Cys)] exhibited normal prenatal course followed by failure to thrive, developmental delay and progressive liver disease. Haplotype analysis identified a shared homozygous region flanking the variant, suggesting a common ancestry. The third individual homozygous for YKT6 [NM_006555.3:c.191A>G p.(Tyr64Cys)] exhibited neurodevelopmental disorders and optic atrophy. Supportive functional data in Drosophila.

Amber rating due to homozygous missense variants and founder effect in two of the families.
Sources: Literature
Mendeliome v1.1675 SEPHS1 Zornitza Stark Marked gene: SEPHS1 as ready
Mendeliome v1.1675 SEPHS1 Zornitza Stark Gene: sephs1 has been classified as Green List (High Evidence).
Mendeliome v1.1675 SEPHS1 Zornitza Stark Classified gene: SEPHS1 as Green List (high evidence)
Mendeliome v1.1675 SEPHS1 Zornitza Stark Gene: sephs1 has been classified as Green List (High Evidence).
Mendeliome v1.1674 SEPHS1 Zornitza Stark gene: SEPHS1 was added
gene: SEPHS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SEPHS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEPHS1 were set to 38531365
Phenotypes for gene: SEPHS1 were set to Neurodevelopmental disorder, MONDO:0700092, SEPHS1-related
Review for gene: SEPHS1 was set to GREEN
Added comment: Nine individuals from eight families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Eight of these individuals had a recurrent variant at amino acid position 371 of SEPHS1 (p.Arg371Trp, p.Arg371Gln, and p.Arg371Gly); seven of these variants were known to be de novo.
Sources: Literature
Mendeliome v1.1673 GLUL Zornitza Stark Phenotypes for gene: GLUL were changed from Glutamine deficiency, congenital MIM#610015; disorder of amino acid metabolism to Developmental and epileptic encephalopathy, MONDO:0100062, GLUL-related; Glutamine deficiency, congenital MIM#610015; disorder of amino acid metabolism
Mendeliome v1.1672 GLUL Zornitza Stark Mode of inheritance for gene: GLUL was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1671 GLUL Zornitza Stark reviewed gene: GLUL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Developmental and epileptic encephalopathy, MONDO:0100062, GLUL-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1671 SCA4_ZFHX3_GGC Bryony Thompson Marked STR: SCA4_ZFHX3_GGC as ready
Mendeliome v1.1671 SCA4_ZFHX3_GGC Bryony Thompson Str: sca4_zfhx3_ggc has been classified as Green List (High Evidence).
Mendeliome v1.1671 SCA4_ZFHX3_GGC Bryony Thompson Classified STR: SCA4_ZFHX3_GGC as Green List (high evidence)
Mendeliome v1.1671 SCA4_ZFHX3_GGC Bryony Thompson Str: sca4_zfhx3_ggc has been classified as Green List (High Evidence).
Mendeliome v1.1670 SCA4_ZFHX3_GGC Bryony Thompson STR: SCA4_ZFHX3_GGC was added
STR: SCA4_ZFHX3_GGC was added to Mendeliome. Sources: Literature
Mode of inheritance for STR: SCA4_ZFHX3_GGC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: SCA4_ZFHX3_GGC were set to 38035881; 38197134
Phenotypes for STR: SCA4_ZFHX3_GGC were set to spinocerebellar ataxia type 4 MONDO:0010847
Review for STR: SCA4_ZFHX3_GGC was set to GREEN
STR: SCA4_ZFHX3_GGC was marked as clinically relevant
Added comment: PMID: 38035881 - repeat expansion is identified in 5 Swedish ataxia families that developed balance and gait disturbances at 15 to 60 years of age and had sensory neuropathy and slow saccades.
PMID: 38197134 - Poly-glycine GGC expansion in the last coding exon of ZFHX3 was identified in the original SCA4 Utah pedigree (Swedish origin) in the region of high linkage identified on 16q22. The expansion was also identified in an Iowa ataxia pedigree of Swedish ancestry. The expansion wasn’t identified in 11,258 exomes, 7,650 WGS probands without neurological phenotype, or 803 individuals with ataxia. Grch38 chr16:72787695–72787758
Normal allele <30 repeats, 21 repeats is the most common (derived from 33,094 individuals)
Undefined pathogenic 30-48 repeats
Definitive pathogenicity 48+ repeats
Sources: Literature
Mendeliome v1.1669 GTF3C5 Bryony Thompson Marked gene: GTF3C5 as ready
Mendeliome v1.1669 GTF3C5 Bryony Thompson Gene: gtf3c5 has been classified as Green List (High Evidence).
Mendeliome v1.1669 GTF3C5 Bryony Thompson Classified gene: GTF3C5 as Green List (high evidence)
Mendeliome v1.1669 GTF3C5 Bryony Thompson Gene: gtf3c5 has been classified as Green List (High Evidence).
Mendeliome v1.1668 GTF3C5 Bryony Thompson gene: GTF3C5 was added
gene: GTF3C5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GTF3C5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTF3C5 were set to 38520561; 35503477
Phenotypes for gene: GTF3C5 were set to neurodevelopmental disorder MONDO:0700092, GTF3C5-related
Review for gene: GTF3C5 was set to GREEN
Added comment: 4 families/probands with syndromic ID. Loss of function is the expected
PMID: 38520561 - Biallelic variants identified (3 missense & 1 stopgain) in 4 individuals from 3 families presenting with multisystem developmental syndrome including the features: growth retardation, developmental delay, intellectual disability, dental anomalies, cerebellar malformations, delayed bone age, skeletal anomalies, and facial dysmorphism. Gene-disease relationship supported by: reduced protein expression in patient cells, yeast assays, and a zebrafish model
PMID: 35503477 - 1 proband with biallelic missense variants and hypomelanosis of Ito, seizures, growth retardation, abnormal brain MRI, developmental delay, and facial dysmorphism
Sources: Literature
Mendeliome v1.1667 MCOLN1 Zornitza Stark Phenotypes for gene: MCOLN1 were changed from Mucolipidosis IV, MIM# 252650; MONDO:0009653 to Mucolipidosis IV, MIM# 252650; MONDO:0009653; Lisch epithelial corneal dystrophy, OMIM# 620763
Mendeliome v1.1666 MCOLN1 Zornitza Stark Publications for gene: MCOLN1 were set to
Mendeliome v1.1665 MCOLN1 Zornitza Stark Mode of inheritance for gene: MCOLN1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1664 MCOLN1 Zornitza Stark edited their review of gene: MCOLN1: Added comment: PMID 37972748: 23 affected individuals from 13 families with Lisch epithelial corneal dystrophy. WGS in 2 families and then targeted Sanger sequencing in the other families identified 9 rare heterozygous loss of function variants in MCOLN1. Homozygous and compound-heterozygous state of 4 of 9 LECD-associated variants cause Mucolipidosis IV (MLIV), which comprises neurodegeneration as well as corneal opacity of infantile-onset with epithelial autofluorescent lysosomal inclusions. Six parents of 3 patients with MLIV confirmed to carry pathogenic MCOLN1 variants did not have the LECD phenotype. Heterozygous MCOLN1 variants can be associated with incomplete penetrance and variable expressivity of LECD with an estimated penetrance of 0.2% for MCOLN1 loss-of-function variants based on gnomAD.; Changed publications: 37972748; Changed phenotypes: Mucolipidosis IV, MIM# 252650, MONDO:0009653, Lisch epithelial corneal dystrophy, OMIM# 620763; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1664 CEP295 Zornitza Stark Marked gene: CEP295 as ready
Mendeliome v1.1664 CEP295 Zornitza Stark Gene: cep295 has been classified as Green List (High Evidence).
Mendeliome v1.1664 PLXNB2 Zornitza Stark Phenotypes for gene: PLXNB2 were changed from Amelogenesis imperfecta MONDO:0019507, PLXNB2 -related; Sensorineural hearing loss disorder MONDO:0020678, PLXNB2 -related to Syndromic disease MONDO:0002254, PLXNB2 -related
Mendeliome v1.1663 PLXNB2 Zornitza Stark Marked gene: PLXNB2 as ready
Mendeliome v1.1663 PLXNB2 Zornitza Stark Gene: plxnb2 has been classified as Green List (High Evidence).
Mendeliome v1.1663 DOCK4 Zornitza Stark Marked gene: DOCK4 as ready
Mendeliome v1.1663 DOCK4 Zornitza Stark Gene: dock4 has been classified as Green List (High Evidence).
Mendeliome v1.1663 DOCK4 Zornitza Stark Classified gene: DOCK4 as Green List (high evidence)
Mendeliome v1.1663 DOCK4 Zornitza Stark Gene: dock4 has been classified as Green List (High Evidence).
Mendeliome v1.1662 TRPV5 Bryony Thompson Marked gene: TRPV5 as ready
Mendeliome v1.1662 TRPV5 Bryony Thompson Gene: trpv5 has been classified as Red List (Low Evidence).
Mendeliome v1.1662 TRPV5 Bryony Thompson Publications for gene: TRPV5 were set to PMID: 38528055
Mendeliome v1.1661 TRPV5 Bryony Thompson Classified gene: TRPV5 as Red List (low evidence)
Mendeliome v1.1661 TRPV5 Bryony Thompson Gene: trpv5 has been classified as Red List (Low Evidence).
Mendeliome v1.1660 TRPV5 Sangavi Sivagnanasundram edited their review of gene: TRPV5: Changed publications: PMID: 38528055, 14679186
Mendeliome v1.1660 TRPV5 Sangavi Sivagnanasundram changed review comment from: Not a well-established gene-disease association. Has only been reported in one consanguineous family.

PMID: 38528055
3 individuals from the same family affected with hypercalciuria.
Biallelic Met598Val variant was identified in the proband and his two affect sibs

Functional assay using WT and mutant plasmid vectors were transfected into HEK293T cells. The assay showed that the mutant vector had a non-functional TRPV5 channel as compared to the WT however no positive control was used.
Sources: Other; to: Not a well-established gene-disease association. Has only been reported in one consanguineous family.

PMID: 38528055
3 individuals from the same family affected with hypercalciuria.
Biallelic Met598Val variant was identified in the proband and his two affect sibs

Functional assay using WT and mutant plasmid vectors were transfected into HEK293T cells. The assay showed that the mutant vector had a non-functional TRPV5 channel as compared to the WT however no positive control was used.

PMID: 14679186
TRPV5 knockout mice model was used to assess whether the abolishment of TRPV5 led to a disruption in Ca2+ handling. The effects of the disruption in Ca2+ handling resulted in bone abnormalities in the mice and is likely the cause of idiopathic hypercalciuria.

Sources: Other
Mendeliome v1.1660 DOCK4 Sangavi Sivagnanasundram gene: DOCK4 was added
gene: DOCK4 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: DOCK4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DOCK4 were set to PMID: 38526744
Phenotypes for gene: DOCK4 were set to DOCK4-related neurodevelopmental disorder (MONDO:0060490)
Review for gene: DOCK4 was set to GREEN
Added comment: 7 unrelated individuals reported with heterozygous variants (missense or null variants) in DOCK4. The individuals either had ID or DD between mild and moderate with brain abnormalities. Two of the individuals are reportedly compound heterozygous.

Functional assay neuro-2A Dock4 knockout cells by using the Alt-R CRISPR-Cas9 system utilizing two different guide RNAs (ko1 and ko2) and one nonspecific control guide RNA (C: control). The assay depicted the loss of function mechanism in the presence of either p.Arg853Leu and p.Asp946_Lys1966delinsValSer* (described as 945VS).
Sources: Other
Mendeliome v1.1660 DISP1 Bryony Thompson Publications for gene: DISP1 were set to 19184110; 26748417; 23542665
Mendeliome v1.1659 DISP1 Bryony Thompson Mode of inheritance for gene: DISP1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1658 DISP1 Bryony Thompson Classified gene: DISP1 as Green List (high evidence)
Mendeliome v1.1658 DISP1 Bryony Thompson Gene: disp1 has been classified as Green List (High Evidence).
Mendeliome v1.1657 DISP1 Sangavi Sivagnanasundram changed review comment from: Well-establised gene disease association with differing mechanism of disease depending on the type of causative variant.
Monoallelic truncating variants that resulted in haploinsufficiency in DISP1 led to mild HPE. However biallelic missense variants that results in a partial loss of function of DISP1 cause HPE as well.

PMID: 38529886
25 individuals from 20 unrelated families with a phenotype associated with mild holoprosencephaly (HPE).
A total of 23 different variants were identified in DISP1 (missense, frameshift and nonsense).
14 heterozygous individuals , 5 compound heterozygous individuals, 6 homozygous individuals (5 of the individuals were from 3 unrelated consanguineous families).

HPE phenotype was also seen prenatally as one of the reported monoallelic individuals was a fetus at 20+6 GW prior to passing due to MTP.

; to: Gene disease association with differing mechanism of disease depending on the type of causative variant.
Monoallelic truncating variants that resulted in haploinsufficiency in DISP1 led to mild HPE. However biallelic missense variants that results in a partial loss of function of DISP1 cause HPE as well.

PMID: 38529886
25 individuals from 20 unrelated families with a phenotype associated with mild holoprosencephaly (HPE).
A total of 23 different variants were identified in DISP1 (missense, frameshift and nonsense).
14 heterozygous individuals , 5 compound heterozygous individuals, 6 homozygous individuals (5 of the individuals were from 3 unrelated consanguineous families).

HPE phenotype was also seen prenatally as one of the reported monoallelic individuals was a fetus at 20+6 GW prior to passing due to MTP.

Mendeliome v1.1657 DISP1 Sangavi Sivagnanasundram changed review comment from: Well-establised gene disease association with differing mechanism of disease depending on the type of causative variant.

PMID: 38529886
25 individuals from 20 unrelated families with a phenotype associated with mild holoprosencephaly (HPE).
A total of 23 different variants were identified in DISP1 (missense, frameshift and nonsense).

Monoallelic truncating variants that resulted in haploinsufficiency in DISP1 led to mild HPE. However biallelic missense variants that results in a partial loss of function f DISP1 cause HPE as well.; to: Well-establised gene disease association with differing mechanism of disease depending on the type of causative variant.
Monoallelic truncating variants that resulted in haploinsufficiency in DISP1 led to mild HPE. However biallelic missense variants that results in a partial loss of function of DISP1 cause HPE as well.

PMID: 38529886
25 individuals from 20 unrelated families with a phenotype associated with mild holoprosencephaly (HPE).
A total of 23 different variants were identified in DISP1 (missense, frameshift and nonsense).
14 heterozygous individuals , 5 compound heterozygous individuals, 6 homozygous individuals (5 of the individuals were from 3 unrelated consanguineous families).

HPE phenotype was also seen prenatally as one of the reported monoallelic individuals was a fetus at 20+6 GW prior to passing due to MTP.

Mendeliome v1.1657 FRYL Ain Roesley Marked gene: FRYL as ready
Mendeliome v1.1657 FRYL Ain Roesley Gene: fryl has been classified as Green List (High Evidence).
Mendeliome v1.1657 FRYL Ain Roesley Classified gene: FRYL as Green List (high evidence)
Mendeliome v1.1657 FRYL Ain Roesley Gene: fryl has been classified as Green List (High Evidence).
Mendeliome v1.1656 FRYL Ain Roesley gene: FRYL was added
gene: FRYL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FRYL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FRYL were set to 38479391
Phenotypes for gene: FRYL were set to neurodevelopmental disorder MONDO:0700092, FRYL-related
Review for gene: FRYL was set to GREEN
gene: FRYL was marked as current diagnostic
Added comment: 14 individuals, all de novo except 1x duo testing (not present in tested father)
5x missense + 8x fs/stopgain + 1x canonical splice

13/13 with ID/DD (1x deceased)
4/14 seizures
7/14 with cardiac anomalies such as PDA, TOF, VSD, dextrocardia

1x also has a de novo fs variant in SF3B4
1x also has a de novo stop gain variant in SDHA

functional studies using flies were performed
Sources: Literature
Mendeliome v1.1655 KCNB2 Ain Roesley Marked gene: KCNB2 as ready
Mendeliome v1.1655 KCNB2 Ain Roesley Gene: kcnb2 has been classified as Green List (High Evidence).
Mendeliome v1.1655 KCNB2 Ain Roesley Classified gene: KCNB2 as Green List (high evidence)
Mendeliome v1.1655 KCNB2 Ain Roesley Gene: kcnb2 has been classified as Green List (High Evidence).
Mendeliome v1.1654 KCNB2 Ain Roesley changed review comment from: 7 individuals, all missense
1x from asymptomatic father

2/5 MRI anomalies
2/5 cardiac anomalies
2/7 urogenital anomalies
7/7 with ID
2/7 epilepsy
2/7 hypotonia
Sources: Literature; to: 7 individuals, all missense
5 de novo + 1x inherited from father who has hypotonia + 1x from asymptomatic father

2/5 MRI anomalies
2/5 cardiac anomalies
2/7 urogenital anomalies
7/7 with ID
2/7 epilepsy
2/7 hypotonia
Sources: Literature
Mendeliome v1.1654 KCNB2 Ain Roesley gene: KCNB2 was added
gene: KCNB2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KCNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNB2 were set to 38503299
Phenotypes for gene: KCNB2 were set to neurodevelopmental disorder MONDO:0700092, KCNB2-related
Review for gene: KCNB2 was set to GREEN
gene: KCNB2 was marked as current diagnostic
Added comment: 7 individuals, all missense
1x from asymptomatic father

2/5 MRI anomalies
2/5 cardiac anomalies
2/7 urogenital anomalies
7/7 with ID
2/7 epilepsy
2/7 hypotonia
Sources: Literature
Mendeliome v1.1653 MAP3K20 Zornitza Stark Phenotypes for gene: MAP3K20 were changed from Centronuclear myopathy 6 with fiber-type disproportion MIM#617760; Split-foot malformation with mesoaxial polydactyly MIM#616890 to Syndromic disease, MONDO:0002254, MAP3K20-related; Centronuclear myopathy 6 with fiber-type disproportion MIM#617760; Split-foot malformation with mesoaxial polydactyly MIM#616890
Mendeliome v1.1652 MAP3K20 Zornitza Stark Publications for gene: MAP3K20 were set to 27816943; 26755636
Mendeliome v1.1651 MAP3K20 Zornitza Stark Mode of inheritance for gene: MAP3K20 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1650 MAP3K20 Zornitza Stark reviewed gene: MAP3K20: Rating: GREEN; Mode of pathogenicity: None; Publications: 38451290; Phenotypes: Syndromic disease, MONDO:0002254, MAP3K20-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1650 PLXNB2 Chirag Patel Classified gene: PLXNB2 as Green List (high evidence)
Mendeliome v1.1650 PLXNB2 Chirag Patel Gene: plxnb2 has been classified as Green List (High Evidence).
Mendeliome v1.1649 CEP295 Chirag Patel Classified gene: CEP295 as Green List (high evidence)
Mendeliome v1.1649 CEP295 Chirag Patel Gene: cep295 has been classified as Green List (High Evidence).
Mendeliome v1.1649 PLXNB2 Chirag Patel gene: PLXNB2 was added
gene: PLXNB2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLXNB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXNB2 were set to PMID: 38458752
Phenotypes for gene: PLXNB2 were set to Amelogenesis imperfecta MONDO:0019507, PLXNB2 -related; Sensorineural hearing loss disorder MONDO:0020678, PLXNB2 -related
Review for gene: PLXNB2 was set to GREEN
gene: PLXNB2 was marked as current diagnostic
Added comment: 8 individuals from 6 families with core features of amelogenesis imperfecta and sensorineural hearing loss. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. WES and WGS identified biallelic pathogenic variants in PLXNB2 (missense, nonsense, splice and a multiexon deletion variants). Variants segregated with disease.

PLXNB2 is a large transmembrane semaphorin receptor protein, and semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Plxnb2 expression was detected in differentiating ameloblasts in mice. Human phenotype overlaps with that seen in Plxnb2 knockout mice.
Sources: Literature
Mendeliome v1.1648 CEP295 Chirag Patel gene: CEP295 was added
gene: CEP295 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CEP295 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP295 were set to PMID: 38154379
Phenotypes for gene: CEP295 were set to Seckel syndrome 11, OMIM # 620767
Review for gene: CEP295 was set to GREEN
gene: CEP295 was marked as current diagnostic
Added comment: 4 children from 2 unrelated families with Seckel-like syndrome - severe primary microcephaly, short stature, developmental delay, intellectual disability, facial deformities, and abnormalities of fingers and toes. WES identified biallelic pathogenic variants in CEP295 gene (p(Q544∗) and p(R1520∗); p(R55Efs∗49) and p(P562L)).

Patient-derived fibroblasts and CEP295-depleted U2OS and RPE1 cells were used to clarify the underlying mechanisms. Depletion of CEP295 resulted in a decrease in the numbers of centrioles and centrosomes and triggered p53-dependent G1 cell cycle arrest. Loss of CEP295 caused extensive primary ciliary defects in both patient-derived fibroblasts and RPE1 cells. The results from complementary experiments revealed that the wild-type CEP295, but not the mutant protein, can correct the developmental defects of the centrosome/centriole and cilia in the patient-derived skin fibroblasts.
Sources: Literature
Mendeliome v1.1647 SASS6 Ain Roesley Publications for gene: SASS6 were set to 24951542; 30639237
Mendeliome v1.1647 SASS6 Ain Roesley Classified gene: SASS6 as Green List (high evidence)
Mendeliome v1.1647 SASS6 Ain Roesley Gene: sass6 has been classified as Green List (High Evidence).
Mendeliome v1.1646 SASS6 Ain Roesley Deleted their comment
Mendeliome v1.1646 SASS6 Ain Roesley commented on gene: SASS6: PMID: 38501757
1x compound het for a fs and +3 splice variant.

Using cDNA RT-ed from mother's RNA, exons 13-15 were amplified and exon 14 was found to be skipped resulting in c.1546_1674del and p.516_558del

PMID: 36739862
1x family, compound het for 2 missense
Functional studies not performed
Mendeliome v1.1646 SASS6 Ain Roesley reviewed gene: SASS6: Rating: GREEN; Mode of pathogenicity: None; Publications: 38501757, 36739862; Phenotypes: Microcephaly 14, primary, autosomal recessive, MIM# 616402; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1646 FANCI Ain Roesley Phenotypes for gene: FANCI were changed from Fanconi anemia, complementation group I, MIM# 609053; MONDO:0012186 to Fanconi anemia, complementation group I, MIM# 609053; MONDO:0012186; primary ovarian failure MONDO:0005387, FANCI-related
Mendeliome v1.1645 FANCI Ain Roesley reviewed gene: FANCI: Rating: AMBER; Mode of pathogenicity: None; Publications: 38483614; Phenotypes: primary ovarian failure MONDO:0005387, FANCI-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1645 CAPNS1 Zornitza Stark Marked gene: CAPNS1 as ready
Mendeliome v1.1645 CAPNS1 Zornitza Stark Gene: capns1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1645 CAPNS1 Zornitza Stark Classified gene: CAPNS1 as Amber List (moderate evidence)
Mendeliome v1.1645 CAPNS1 Zornitza Stark Gene: capns1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1644 CAPNS1 Zornitza Stark gene: CAPNS1 was added
gene: CAPNS1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CAPNS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAPNS1 were set to 38230350
Phenotypes for gene: CAPNS1 were set to Hereditary pulmonary arterial hypertension MONDO:0017148, CAPNS1-related
Review for gene: CAPNS1 was set to AMBER
Added comment: Three individuals from two families reported with homozygous splice site variants.
Sources: Expert list
Mendeliome v1.1643 USP27X Zornitza Stark Phenotypes for gene: USP27X were changed from Mental retardation, X-linked 105, MIM#300984 to Intellectual disability, X-linked 105, MIM#300984
Mendeliome v1.1642 USP27X Zornitza Stark Publications for gene: USP27X were set to 25644381
Mendeliome v1.1641 USP27X Zornitza Stark Classified gene: USP27X as Green List (high evidence)
Mendeliome v1.1641 USP27X Zornitza Stark Gene: usp27x has been classified as Green List (High Evidence).
Mendeliome v1.1640 USP27X Zornitza Stark edited their review of gene: USP27X: Added comment: Ten additional individuals and further experimental data reported.; Changed rating: GREEN; Changed publications: 25644381, 38182161; Changed phenotypes: Intellectual disability, X-linked 105, MIM#300984
Mendeliome v1.1640 ZNF143 Bryony Thompson Classified gene: ZNF143 as Amber List (moderate evidence)
Mendeliome v1.1640 ZNF143 Bryony Thompson Gene: znf143 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1639 ZNF143 Bryony Thompson reviewed gene: ZNF143: Rating: AMBER; Mode of pathogenicity: None; Publications: 27349184, 33845046, 9009278, 22268977, 27349184, 27349184; Phenotypes: methylmalonic aciduria and homocystinuria MONDO:0016826; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1639 TCN1 Bryony Thompson Marked gene: TCN1 as ready
Mendeliome v1.1639 TCN1 Bryony Thompson Gene: tcn1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1639 TCN1 Bryony Thompson Classified gene: TCN1 as Amber List (moderate evidence)
Mendeliome v1.1639 TCN1 Bryony Thompson Gene: tcn1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1638 TCN1 Bryony Thompson gene: TCN1 was added
gene: TCN1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TCN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TCN1 were set to 29764838; 19686235
Phenotypes for gene: TCN1 were set to transcobalamin I deficiency MONDO:0008659
Review for gene: TCN1 was set to AMBER
Added comment: Unclear if TC1 deficiency is associated with a clinical phenotype and only found 2 families with genetic findings. 1 confirmed chet (2 truncating variants) with severe TC 1 deficiency (depression and anxiety only reported symptoms, had sickle cell trait) & another family with 2 siblings that are presumed homozygous for a truncating variant (no plasma or serum TC 1 levels but no DNA available for genetic testing) which was found heterozygous in multiple first-degree relatives. Unclear if there is a clinical phenotype. Heterozygous individuals displayed mildly low or low-normal TC 1 serum levels. Also, 4 homozygotes were identified in a study of a loss-of-function variant associated with lower vitamin B12 concentration in African Americans but there was limited ability to assess the clinical impact of the recessive disease
Sources: Literature
Mendeliome v1.1637 FEM1B Zornitza Stark Classified gene: FEM1B as Green List (high evidence)
Mendeliome v1.1637 FEM1B Zornitza Stark Gene: fem1b has been classified as Green List (High Evidence).
Mendeliome v1.1636 FEM1B Zornitza Stark Publications for gene: FEM1B were set to PMID: 31036916
Mendeliome v1.1635 FEM1B Zornitza Stark Phenotypes for gene: FEM1B were changed from Syndromic intellectual disability to Syndromic disease MONDO:0002254, FEM1B-related
Mendeliome v1.1634 FEM1B Zornitza Stark edited their review of gene: FEM1B: Added comment: Five individuals reported now with same recurrent missense variant, NM_015322.5:c.377G>A NP_056137.1:p.(Arg126Gln). Affected individuals shared a severe neurodevelopmental disorder with behavioral phenotypes and a variable set of malformations, including brain anomalies, clubfeet, skeletal abnormalities, and facial dysmorphism. Overexpression of the the FEM1BR126Q variant but not FEM1B wild-type protein, during mouse brain development, resulted in delayed neuronal migration of the target cells.; Changed rating: GREEN; Changed publications: 31036916, 38465576; Changed phenotypes: Syndromic disease MONDO:0002254, FEM1B-related; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1634 DISP1 Sangavi Sivagnanasundram reviewed gene: DISP1: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 38529886; Phenotypes: Holoprosencephaly (MONDO:0016296); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1634 TRPV5 Sangavi Sivagnanasundram gene: TRPV5 was added
gene: TRPV5 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: TRPV5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRPV5 were set to PMID: 38528055
Phenotypes for gene: TRPV5 were set to TRPV5-related hypercalciuria (MONDO:0009550)
Review for gene: TRPV5 was set to RED
Added comment: Not a well-established gene-disease association. Has only been reported in one consanguineous family.

PMID: 38528055
3 individuals from the same family affected with hypercalciuria.
Biallelic Met598Val variant was identified in the proband and his two affect sibs

Functional assay using WT and mutant plasmid vectors were transfected into HEK293T cells. The assay showed that the mutant vector had a non-functional TRPV5 channel as compared to the WT however no positive control was used.
Sources: Other
Mendeliome v1.1634 USP14 Zornitza Stark Marked gene: USP14 as ready
Mendeliome v1.1634 USP14 Zornitza Stark Gene: usp14 has been classified as Green List (High Evidence).
Mendeliome v1.1634 USP14 Zornitza Stark Classified gene: USP14 as Green List (high evidence)
Mendeliome v1.1634 USP14 Zornitza Stark Gene: usp14 has been classified as Green List (High Evidence).
Mendeliome v1.1633 USP14 Zornitza Stark gene: USP14 was added
gene: USP14 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: USP14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USP14 were set to 38469793; 35066879
Phenotypes for gene: USP14 were set to Syndromic disease MONDO:0002254, USP14-related
Review for gene: USP14 was set to GREEN
Added comment: PMID 35066879: 3 fetuses from 2 different branches of a consanguineous family, presenting with distal arthrogryposis, underdevelopment of the corpus callosum, and dysmorphic facial features. Exome sequencing identified a biallelic 4-bp deletion (c.233_236delTTCC; p.Leu78Glnfs*11) in USP14, and sequencing of family members showed segregation with the phenotype. Ubiquitin-specific protease 14 (USP14) encodes a major proteasome-associated deubiquitinating enzyme with an established dual role as an inhibitor and an activator of proteolysis, maintaining protein homeostasis. Usp14-deficient mice show a phenotype similar to lethal human multiple congenital contractures phenotypes, with callosal anomalies, muscle wasting, and early lethality, attributed to neuromuscular junction defects due to decreased monomeric ubiquitin pool. RT-qPCR experiment in an unaffected heterozygote revealed that mutant USP14 was expressed, indicating that abnormal transcript escapes nonsense-mediated mRNA decay.

PMID 38469793: biallelic USP14 variants in four individuals from three unrelated families: one fetus, a newborn with a syndromic NDD, and two siblings affected by a progressive neurological disease. Specifically, the two siblings from the latter family carried two compound heterozygous variants c.8T>C p.(Leu3Pro) and c.988C>T p.(Arg330*), while the fetus had a homozygous frameshift c.899_902del p.(Lys300Serfs*24) variant and the newborn patient harbored a homozygous frameshift c.233_236del p.(Leu78Glnfs*11) variant. The fetus and the newborn had extensive brain malformations.
Sources: Literature
Mendeliome v1.1632 ZFX Zornitza Stark Phenotypes for gene: ZFX were changed from Neurodevelopmental disorder, MONDO:0700092, ZFX-related to Intellectual developmental disorder, X-linked syndromic 37, MIM# 301118
Mendeliome v1.1631 ZFX Zornitza Stark edited their review of gene: ZFX: Changed phenotypes: Intellectual developmental disorder, X-linked syndromic 37, MIM# 301118
Mendeliome v1.1631 PRDX1 Bryony Thompson Marked gene: PRDX1 as ready
Mendeliome v1.1631 PRDX1 Bryony Thompson Gene: prdx1 has been classified as Green List (High Evidence).
Mendeliome v1.1631 PRDX1 Bryony Thompson Classified gene: PRDX1 as Green List (high evidence)
Mendeliome v1.1631 PRDX1 Bryony Thompson Gene: prdx1 has been classified as Green List (High Evidence).
Mendeliome v1.1630 PRDX1 Bryony Thompson gene: PRDX1 was added
gene: PRDX1 was added to Mendeliome. Sources: Literature
digenic tags were added to gene: PRDX1.
Mode of inheritance for gene: PRDX1 was set to Other
Publications for gene: PRDX1 were set to 29302025; 35190856
Phenotypes for gene: PRDX1 were set to methylmalonic aciduria and homocystinuria type cblC MONDO:0010184
Mode of pathogenicity for gene: PRDX1 was set to Other
Review for gene: PRDX1 was set to GREEN
Added comment: Only variants affecting the canonical splice acceptor site of intron 5 (e.g. c.515-1G-T, c.515-2A-T) that cause skipping of exon 6 and the polyA termination signal of PRDX1 produce an MMACHC epimutation. The resulting read-through transcript extends through the adjacent MMACHC locus in the antisense orientation. These PRDX1 exon 6 acceptor splice site variants cause disease through digenic inheritance with a pathogenic MMACHC on the other allele.
Sources: Literature
Mendeliome v1.1629 PSMB10 Zornitza Stark Phenotypes for gene: PSMB10 were changed from Proteasome-associated autoinflammatory syndrome 5, MIM# 619175 to Proteasome-associated autoinflammatory syndrome 5, MIM# 619175; Severe combined immunodeficiency, MONDO:0015974, PSMB10-related
Mendeliome v1.1628 PSMB10 Zornitza Stark Publications for gene: PSMB10 were set to 31783057; 37600812
Mendeliome v1.1627 PSMB10 Zornitza Stark Mode of inheritance for gene: PSMB10 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1626 PSMB10 Zornitza Stark edited their review of gene: PSMB10: Added comment: PMID 38503300: Six individuals with three de novo missense variants. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash.; Changed publications: 31783057, 37600812, 38503300; Changed phenotypes: Proteasome-associated autoinflammatory syndrome 5, MIM# 619175, Severe combined immunodeficiency, MONDO:0015974, PSMB10-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1626 CST3 Bryony Thompson Classified gene: CST3 as Green List (high evidence)
Mendeliome v1.1626 CST3 Bryony Thompson Gene: cst3 has been classified as Green List (High Evidence).
Mendeliome v1.1625 CST3 Bryony Thompson reviewed gene: CST3: Rating: GREEN; Mode of pathogenicity: Other; Publications: 38489591; Phenotypes: leukodystrophy MONDO:0019046, CST3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1625 SLC32A1 Zornitza Stark Phenotypes for gene: SLC32A1 were changed from Generalized epilepsy with febrile seizures plus, type 12, MIM# 620755 to Generalized epilepsy with febrile seizures plus, type 12, MIM# 620755; Developmental and epileptic encephalopathy 114, MIM# 620774
Mendeliome v1.1624 SLC32A1 Zornitza Stark edited their review of gene: SLC32A1: Changed phenotypes: Generalized epilepsy with febrile seizures plus, type 12, MIM# 620755, Developmental and epileptic encephalopathy 114, MIM# 620774
Mendeliome v1.1624 CRELD1 Zornitza Stark Phenotypes for gene: CRELD1 were changed from Developmental and epileptic encephalopathy, MONDO:0100062, CRELD1-related; Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217 to Jeffries-Lakhani neurodevelopmental syndrome, MIM# 620771; Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217
Mendeliome v1.1623 CRELD1 Zornitza Stark edited their review of gene: CRELD1: Changed phenotypes: Jeffries-Lakhani neurodevelopmental syndrome, MIM# 620771, Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217
Mendeliome v1.1623 EHHADH Bryony Thompson Publications for gene: EHHADH were set to 24401050
Mendeliome v1.1622 EHHADH Bryony Thompson Classified gene: EHHADH as Green List (high evidence)
Mendeliome v1.1622 EHHADH Bryony Thompson Gene: ehhadh has been classified as Green List (High Evidence).
Mendeliome v1.1621 EHHADH Bryony Thompson reviewed gene: EHHADH: Rating: GREEN; Mode of pathogenicity: None; Publications: 35738466, 38310177, 24401050; Phenotypes: Fanconi renotubular syndrome 3 MONDO:0014275; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1621 RXFP2 Katie Ayers reviewed gene: RXFP2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 37208861, 38430325; Phenotypes: Infertility, cryptorchidism, non-obstructive azoospermia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1621 KAT6B Ain Roesley Phenotypes for gene: KAT6B were changed from SBBYSS syndrome MIM#603736; Genitopatellar syndrome MIM#606170 to SBBYSS syndrome MIM#603736; Genitopatellar syndrome MIM#606170; KAT6B-related multiple congenital anomalies syndrome MONDO:0036042
Mendeliome v1.1620 SV2A Zornitza Stark Phenotypes for gene: SV2A were changed from Neurodevelopmental disorder, MONDO:0700092, SV2A-related to Neurodevelopmental disorder, MONDO:0700092, SV2A-related; Developmental and epileptic encephalopathy 113, MIM# 620772
Mendeliome v1.1619 SV2A Zornitza Stark edited their review of gene: SV2A: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, SV2A-related, Developmental and epileptic encephalopathy 113, MIM# 620772
Mendeliome v1.1619 GNE Zornitza Stark Phenotypes for gene: GNE were changed from Nonaka myopathy 605820; Sialuria MIM#269921; ADUDP-GlcNAc epimerase/kinase deficiency (Disorders of multiple glycosylation and other glycosylation pathways) to Thrombocytopenia 12 with or without myopathy, MIM#620757; Nonaka myopathy 605820; Sialuria MIM#269921; ADUDP-GlcNAc epimerase/kinase deficiency (Disorders of multiple glycosylation and other glycosylation pathways)
Mendeliome v1.1618 GNE Zornitza Stark edited their review of gene: GNE: Changed phenotypes: Thrombocytopenia 12 with or without myopathy, MIM#620757, Nonaka myopathy 605820, Sialuria MIM#269921, ADUDP-GlcNAc epimerase/kinase deficiency (Disorders of multiple glycosylation and other glycosylation pathways)
Mendeliome v1.1618 SAMD7 Zornitza Stark Phenotypes for gene: SAMD7 were changed from Macular dystrophy, retinal, SAMD7-related MONDO:0031166 to Macular dystrophy with or without cone dysfunction, MIM# 620762
Mendeliome v1.1617 SAMD7 Zornitza Stark reviewed gene: SAMD7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Macular dystrophy with or without cone dysfunction, MIM# 620762; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1617 FHL2 Zornitza Stark Marked gene: FHL2 as ready
Mendeliome v1.1617 FHL2 Zornitza Stark Gene: fhl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1617 FHL2 Zornitza Stark Classified gene: FHL2 as Amber List (moderate evidence)
Mendeliome v1.1617 FHL2 Zornitza Stark Gene: fhl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1616 FHL2 Zornitza Stark gene: FHL2 was added
gene: FHL2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FHL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FHL2 were set to 36854411; 25358972
Phenotypes for gene: FHL2 were set to Cardiomyopathy, MONDO:0004994, FHL2-related
Review for gene: FHL2 was set to AMBER
Added comment: Emerging evidence that variants in this gene may be associated with cardiomyopathy.

Reports of HCM and DCM.

c.391C>T (p.Arg131Cys) may be recurrent in early-onset DCM.
Sources: Expert Review
Mendeliome v1.1615 ZFHX3 Zornitza Stark Publications for gene: ZFHX3 were set to
Mendeliome v1.1614 ZRSR2 Zornitza Stark Marked gene: ZRSR2 as ready
Mendeliome v1.1614 ZRSR2 Zornitza Stark Gene: zrsr2 has been classified as Green List (High Evidence).
Mendeliome v1.1614 ZRSR2 Zornitza Stark Classified gene: ZRSR2 as Green List (high evidence)
Mendeliome v1.1614 ZRSR2 Zornitza Stark Gene: zrsr2 has been classified as Green List (High Evidence).
Mendeliome v1.1613 ZRSR2 Zornitza Stark gene: ZRSR2 was added
gene: ZRSR2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: ZRSR2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: ZRSR2 were set to 38158857
Phenotypes for gene: ZRSR2 were set to Orofacialdigital syndrome MONDO:0015375, ZRSR2-related
Review for gene: ZRSR2 was set to GREEN
Added comment: Oral-facial-digital (OFD) syndrome with brain anomalies ranging from alobar holoprosencephaly to pituitary anomalies.
Six unrelated families with two truncating variants and functional studies:
- p.(Gly404GlufsTer23): detected in one family with 2x affected males
- p.(Arg403GlyfsTer24): 5 unrelated families, both de novo and inherited
Sources: Expert Review
Mendeliome v1.1612 SLC32A1 Zornitza Stark Phenotypes for gene: SLC32A1 were changed from Genetic epilepsy with febrile seizures plus; Developmental and epileptic encephalopathy MONDO:0100062, SLC32A1-related to Generalized epilepsy with febrile seizures plus, type 12, MIM# 620755
Mendeliome v1.1611 SLC32A1 Zornitza Stark edited their review of gene: SLC32A1: Changed phenotypes: Generalized epilepsy with febrile seizures plus, type 12, MIM# 620755
Mendeliome v1.1611 PTRHD1 Zornitza Stark Phenotypes for gene: PTRHD1 were changed from Parkinsonism; Intellectual disability to Neurodevelopmental disorder with early-onset parkinsonism and behavioral abnormalities, MIM# 620747
Mendeliome v1.1610 BBS4 Bryony Thompson reviewed gene: BBS4: Rating: RED; Mode of pathogenicity: None; Publications: 37588201; Phenotypes: autosomal dominant polycystic liver disease MONDO:0000447; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1610 BBS4 Bryony Thompson Deleted their review
Mendeliome v1.1610 ZFHX3 Lucy Spencer reviewed gene: ZFHX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 38412861; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), ZFHX3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1610 EFEMP1 Zornitza Stark Phenotypes for gene: EFEMP1 were changed from Glaucoma 1, open angle, H, MIM# 611276; Doyne honeycomb degeneration of retina, MIM# 126600; EFEMP1-related connective tissue disorder to Glaucoma 1, open angle, H, MIM# 611276; Doyne honeycomb degeneration of retina, MIM# 126600; EFEMP1-related connective tissue disorder
Mendeliome v1.1609 EFEMP1 Zornitza Stark Phenotypes for gene: EFEMP1 were changed from Doyne honeycomb degeneration of retina, MIM# 126600; EFEMP1-related connective tissue disorder to Glaucoma 1, open angle, H, MIM# 611276; Doyne honeycomb degeneration of retina, MIM# 126600; EFEMP1-related connective tissue disorder
Mendeliome v1.1608 EFEMP1 Zornitza Stark edited their review of gene: EFEMP1: Changed phenotypes: Doyne honeycomb degeneration of retina, MIM# 126600, EFEMP1-related connective tissue disorder, Glaucoma 1, open angle, H, MIM# 611276
Mendeliome v1.1608 SLC4A10 Zornitza Stark Phenotypes for gene: SLC4A10 were changed from Neurodevelopmental disorderMONDO:0700092, SLC4A10-related to Neurodevelopmental disorder with hypotonia and characteristic brain abnormalities, MIM# 620746
Mendeliome v1.1607 SLC4A10 Zornitza Stark reviewed gene: SLC4A10: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with hypotonia and characteristic brain abnormalities, MIM# 620746; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1607 RREB1 Zornitza Stark Phenotypes for gene: RREB1 were changed from Noonan syndrome-like disorder to Rasopathy, MONDO:0021060, RREB1-related
Mendeliome v1.1606 RGS6 Zornitza Stark Phenotypes for gene: RGS6 were changed from Cataract,MONDO:0005129; intellectual disability, MONDO:0001071; microcephaly, MONDO:0001149 to Neurodevelopmental disorder, MONDO:0700092, RGS6-related
Mendeliome v1.1605 ZSCAN10 Zornitza Stark Marked gene: ZSCAN10 as ready
Mendeliome v1.1605 ZSCAN10 Zornitza Stark Gene: zscan10 has been classified as Green List (High Evidence).
Mendeliome v1.1605 ZSCAN10 Zornitza Stark Classified gene: ZSCAN10 as Green List (high evidence)
Mendeliome v1.1605 ZSCAN10 Zornitza Stark Gene: zscan10 has been classified as Green List (High Evidence).
Mendeliome v1.1604 CORIN Zornitza Stark Phenotypes for gene: CORIN were changed from Preeclampsia/eclampsia 5 MIM#614595; ?Cardiomyopathy, familial hypertrophic, 30, atrial (MIM:620734) to Preeclampsia/eclampsia 5 MIM#614595; Cardiomyopathy, familial hypertrophic, 30, atrial (MIM:620734)
Mendeliome v1.1603 CORIN Zornitza Stark Publications for gene: CORIN were set to 22437503
Mendeliome v1.1602 CORIN Zornitza Stark Phenotypes for gene: CORIN were changed from Preeclampsia/eclampsia 5 MIM#614595 to Preeclampsia/eclampsia 5 MIM#614595; ?Cardiomyopathy, familial hypertrophic, 30, atrial (MIM:620734)
Mendeliome v1.1601 CELSR3 Zornitza Stark Marked gene: CELSR3 as ready
Mendeliome v1.1601 CELSR3 Zornitza Stark Gene: celsr3 has been classified as Green List (High Evidence).
Mendeliome v1.1601 CELSR3 Zornitza Stark Classified gene: CELSR3 as Green List (high evidence)
Mendeliome v1.1601 CELSR3 Zornitza Stark Gene: celsr3 has been classified as Green List (High Evidence).
Mendeliome v1.1600 CIAO1 Zornitza Stark Marked gene: CIAO1 as ready
Mendeliome v1.1600 CIAO1 Zornitza Stark Gene: ciao1 has been classified as Green List (High Evidence).
Mendeliome v1.1600 CIAO1 Zornitza Stark Phenotypes for gene: CIAO1 were changed from Neuromuscular disease, CIAO1-related (MONDO:0019056) to Neurodegenerative disease, MONDO:0005559, CIAO1-related
Mendeliome v1.1599 CIAO1 Zornitza Stark Classified gene: CIAO1 as Green List (high evidence)
Mendeliome v1.1599 CIAO1 Zornitza Stark Gene: ciao1 has been classified as Green List (High Evidence).
Mendeliome v1.1598 MMS19 Zornitza Stark Marked gene: MMS19 as ready
Mendeliome v1.1598 MMS19 Zornitza Stark Gene: mms19 has been classified as Red List (Low Evidence).
Mendeliome v1.1598 MMS19 Zornitza Stark Phenotypes for gene: MMS19 were changed from Neuromuscular disease, MMS19-related (MONDO:0019056) to Neurodegenerative disease, MONDO:0005559, MMS19-related
Mendeliome v1.1597 MMS19 Zornitza Stark Classified gene: MMS19 as Red List (low evidence)
Mendeliome v1.1597 MMS19 Zornitza Stark Gene: mms19 has been classified as Red List (Low Evidence).
Mendeliome v1.1596 NARS Zornitza Stark changed review comment from: AR disorder: assessed as LIMITED by ClinGen (borderline MODERATE).; to: Both MOIs assessed as MODERATE by ClinGen.
Mendeliome v1.1596 CIAO1 Paul De Fazio changed review comment from: PMID:38196629 (note pre-print) describes 4 unrelated patients with core features of progressive muscle weakness, respiratory insufficiency, joint hyperlaxity, ankle tightness, calf pseudohypertrophy, elevated CK, and larning disabilities/difficulties. 2 patients presented with increased iron deposition in the brain. Age of recognition of myopathic symptoms varied from early childhood to adolescence.

PMID: 38411040 reports 2 unrelated patients. Patient 1 was born with microcephaly and borderline hypertonia, and died at 18 months of respiratory failure from bronchiolitis. Patient 2 presented with failure to thrive, a hyperkinetic movement disorder, and autism before deteriorating in late teens with muscle weakness, recurrent pneuomonia with respiratory insufficiency, and eventually death due to multi-organ failure with carnificating pneumonia, septic cardiomyopathy, and intracranial hemorrhages. Immune deficiency was ruled out.

All variants reported were homozygous or compound heterozygous missense variants, with the exception of one large in-frame deletion of exon 7. Cell line studies showed the variants resulted in reduced protein stability and downstream cellular defects which could be rescued by wild-type CIAO1.
Sources: Literature; to: PMID:38196629 (note pre-print) describes 4 unrelated patients with core features of progressive muscle weakness, respiratory insufficiency, joint hyperlaxity, ankle tightness, calf pseudohypertrophy, elevated CK, and larning disabilities/difficulties. 2 patients presented with increased iron deposition in the brain. Age of recognition of myopathic symptoms varied from early childhood to adolescence. Muscle biopsy showed variation in fiber size and an increase in internalized nuclei, as well as scattered degenerating/regenerating fibers and a mild to minimal increase in endomysial fibrosis. Electron microscopy revealed morphologically abnormal mitochondria.

PMID: 38411040 reports 2 unrelated patients. Patient 1 was born with microcephaly and borderline hypertonia, and died at 18 months of respiratory failure from bronchiolitis. Patient 2 presented with failure to thrive, a hyperkinetic movement disorder, and autism before deteriorating in late teens with muscle weakness, recurrent pneuomonia with respiratory insufficiency, and eventually death due to multi-organ failure with carnificating pneumonia, septic cardiomyopathy, and intracranial hemorrhages. Immune deficiency was ruled out.

All variants reported were homozygous or compound heterozygous missense variants, with the exception of one large in-frame deletion of exon 7. Cell line studies showed the variants resulted in reduced protein stability and downstream cellular defects which could be rescued by wild-type CIAO1.
Mendeliome v1.1596 MMS19 Paul De Fazio gene: MMS19 was added
gene: MMS19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MMS19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MMS19 were set to 38411040
Phenotypes for gene: MMS19 were set to Neuromuscular disease, MMS19-related (MONDO:0019056)
Penetrance for gene: MMS19 were set to unknown
Review for gene: MMS19 was set to RED
gene: MMS19 was marked as current diagnostic
Added comment: Single patient reported with postnatal microcephaly, bilateral cataracts, failure to thrive, progressive spastic tetraparesis, scoliosis, myoclonic epilepsy and precocious puberty. Cerebral MRI at age 4 years showed pontocerebellar atrophy and white matter abnormalities. Patient died age 13 after recurrent respiratory tract infections. A homozygous in-frame deletion p.(Glu213del) was identified. Cell line studies supported pathogenicity of the variant. A zebrafish knockout model also showed a detrimental effect of Mms19 deficincy.
Sources: Literature
Mendeliome v1.1596 CIAO1 Paul De Fazio gene: CIAO1 was added
gene: CIAO1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CIAO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CIAO1 were set to 38411040; 38196629
Phenotypes for gene: CIAO1 were set to Neuromuscular disease, CIAO1-related (MONDO:0019056)
Penetrance for gene: CIAO1 were set to unknown
Review for gene: CIAO1 was set to GREEN
gene: CIAO1 was marked as current diagnostic
Added comment: PMID:38196629 (note pre-print) describes 4 unrelated patients with core features of progressive muscle weakness, respiratory insufficiency, joint hyperlaxity, ankle tightness, calf pseudohypertrophy, elevated CK, and larning disabilities/difficulties. 2 patients presented with increased iron deposition in the brain. Age of recognition of myopathic symptoms varied from early childhood to adolescence.

PMID: 38411040 reports 2 unrelated patients. Patient 1 was born with microcephaly and borderline hypertonia, and died at 18 months of respiratory failure from bronchiolitis. Patient 2 presented with failure to thrive, a hyperkinetic movement disorder, and autism before deteriorating in late teens with muscle weakness, recurrent pneuomonia with respiratory insufficiency, and eventually death due to multi-organ failure with carnificating pneumonia, septic cardiomyopathy, and intracranial hemorrhages. Immune deficiency was ruled out.

All variants reported were homozygous or compound heterozygous missense variants, with the exception of one large in-frame deletion of exon 7. Cell line studies showed the variants resulted in reduced protein stability and downstream cellular defects which could be rescued by wild-type CIAO1.
Sources: Literature
Mendeliome v1.1596 THBS2 Ain Roesley Phenotypes for gene: THBS2 were changed from {Lumbar disc herniation, susceptibility to} 603932 to {Lumbar disc herniation, susceptibility to} 603932; connective tissue disorder MONDO:0003900, THBS2-related
Mendeliome v1.1595 THBS2 Ain Roesley Publications for gene: THBS2 were set to
Mendeliome v1.1594 THBS2 Ain Roesley Mode of inheritance for gene: THBS2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1594 THBS2 Ain Roesley Classified gene: THBS2 as Amber List (moderate evidence)
Mendeliome v1.1594 THBS2 Ain Roesley Gene: thbs2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1593 THBS2 Chris Ciotta reviewed gene: THBS2: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 38433265; Phenotypes: connective tissue disorder MONDO:0003900, THBS2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1593 UBAP1L Seb Lunke Marked gene: UBAP1L as ready
Mendeliome v1.1593 UBAP1L Seb Lunke Gene: ubap1l has been classified as Green List (High Evidence).
Mendeliome v1.1593 UBAP1L Seb Lunke Classified gene: UBAP1L as Green List (high evidence)
Mendeliome v1.1593 UBAP1L Seb Lunke Gene: ubap1l has been classified as Green List (High Evidence).
Mendeliome v1.1592 UBAP1L Seb Lunke Classified gene: UBAP1L as Green List (high evidence)
Mendeliome v1.1592 UBAP1L Seb Lunke Gene: ubap1l has been classified as Green List (High Evidence).
Mendeliome v1.1591 DIP2C Elena Savva Marked gene: DIP2C as ready
Mendeliome v1.1591 DIP2C Elena Savva Gene: dip2c has been classified as Green List (High Evidence).
Mendeliome v1.1591 APOLD1 Seb Lunke Marked gene: APOLD1 as ready
Mendeliome v1.1591 APOLD1 Seb Lunke Gene: apold1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1591 TOGARAM2 Zornitza Stark Marked gene: TOGARAM2 as ready
Mendeliome v1.1591 TOGARAM2 Zornitza Stark Gene: togaram2 has been classified as Red List (Low Evidence).
Mendeliome v1.1591 APOLD1 Seb Lunke Classified gene: APOLD1 as Amber List (moderate evidence)
Mendeliome v1.1591 APOLD1 Seb Lunke Gene: apold1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1590 DIP2C Elena Savva Classified gene: DIP2C as Green List (high evidence)
Mendeliome v1.1590 DIP2C Elena Savva Gene: dip2c has been classified as Green List (High Evidence).
Mendeliome v1.1590 TOGARAM2 Zornitza Stark Classified gene: TOGARAM2 as Red List (low evidence)
Mendeliome v1.1590 TOGARAM2 Zornitza Stark Gene: togaram2 has been classified as Red List (Low Evidence).
Mendeliome v1.1589 UBAP1L Ee Ming Wong changed review comment from: - Twelve unrelated families with Hungary, the United States, Israel, Tunisia and the Netherlands with members presenting with autosomal recessive rod-cone or cone-rod dystrophy
- Reported variants included splice, nonsense, frameshift and in-frame del variants
- Age of disease onset was very variable, with some patients experiencing first symptoms during their fourth decade of life or later.
Sources: Literature; to: - Twelve unrelated families with Hungary, the United States, Israel, Tunisia and the Netherlands with members presenting with autosomal recessive rod-cone or cone-rod dystrophy
- Reported variants included splice, nonsense, frameshift and in-frame del variants
- Age of disease onset was very variable, with some patients experiencing first symptoms during their fourth decade of life or later.
Sources: Literature
Mendeliome v1.1589 CORIN Daniel Flanagan reviewed gene: CORIN: Rating: RED; Mode of pathogenicity: None; Publications: 37913506, 15637153; Phenotypes: ?Cardiomyopathy, familial hypertrophic, 30, atrial (MIM:620734); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1589 SNUPN Seb Lunke Marked gene: SNUPN as ready
Mendeliome v1.1589 SNUPN Seb Lunke Gene: snupn has been classified as Green List (High Evidence).
Mendeliome v1.1589 TOGARAM2 Zornitza Stark Classified gene: TOGARAM2 as Red List (low evidence)
Mendeliome v1.1589 TOGARAM2 Zornitza Stark Gene: togaram2 has been classified as Red List (Low Evidence).
Mendeliome v1.1588 UBAP1L Ee Ming Wong gene: UBAP1L was added
gene: UBAP1L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UBAP1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBAP1L were set to PMID: 38293907; 38420906
Phenotypes for gene: UBAP1L were set to Cone-rod dystrophy (MONDO:0015993), UBAP1L-related
Review for gene: UBAP1L was set to GREEN
gene: UBAP1L was marked as current diagnostic
Added comment: - Twelve unrelated families with Hungary, the United States, Israel, Tunisia and the Netherlands with members presenting with autosomal recessive rod-cone or cone-rod dystrophy
- Reported variants included splice, nonsense, frameshift and in-frame del variants
- Age of disease onset was very variable, with some patients experiencing first symptoms during their fourth decade of life or later.
Sources: Literature
Mendeliome v1.1588 SNUPN Seb Lunke Classified gene: SNUPN as Green List (high evidence)
Mendeliome v1.1588 SNUPN Seb Lunke Gene: snupn has been classified as Green List (High Evidence).
Mendeliome v1.1587 CELSR3 Crystle Lee gene: CELSR3 was added
gene: CELSR3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CELSR3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CELSR3 were set to PMID: 38429302
Phenotypes for gene: CELSR3 were set to Neurodevelopmental disorder (MONDO#0700092), CELSR3-related
Review for gene: CELSR3 was set to GREEN
Added comment: PMID: 38429302:12 affected individuals from 11 families reported with bi-allelic variants. Phenotype ranged from CNS anomalies (7/12), CNS and CAKUT (3/12) and CAKUT only (2/12). Only missense variants reported and 1 inframe variant. Functional studies done in zebrafish demonstrate similar structural anomalies of the developing pronephros and neuronal abnormalities to affected individuals

PMID: 34951123: 5 het missense variants reported in patients with febrile seizures (FS)/epilepsy. Arg3141Gln present in gnomAD (7 hets). No functional studies. Summarised as potentially associated with febrile seizures (FS)/epilepsy
Sources: Literature
Mendeliome v1.1587 APOLD1 Lucy Spencer changed review comment from: PMID: 35638551
1 family with an atypical inherited bleeding disorder characterised by severe spontaneous bleeding episodes in childhood and microcirculatory problems. 4 affected individuals across 2 generations have R49*in APOLD1, another affected individual from a third generation was not able to be sequenced = 4 meiosis. 4 unaffected individuals did not have the variant.

This gene has no NMD region, R49* would affect 82% of the protein. Paper is not using the MANE select transcript, alt p. in MANE select is R18* which affects 92% of the MANE select protein

Interestingly R49* is created by a delins/2 missense in cis, 1 common R49Q and 1 rare R49W, some UNaffected family members just have the common missense without the other in cis.

Immunofluorescence studies in patient platelets showed a 50% reduction of APOLD1 and disrupted cytoskeletal and junctional organization.
Sources: Literature; to: PMID: 35638551
1 family with an atypical inherited bleeding disorder characterised by severe spontaneous bleeding episodes in childhood and microcirculatory problems. 4 affected individuals across 2 generations have R49*in APOLD1, another affected individual from a third generation was not able to be sequenced = 4 meiosis. 4 unaffected individuals did not have the variant.

This gene has no NMD region, R49* would affect 82% of the protein. Paper is not using the MANE select transcript, alt p. in MANE select is R18* which affects 92% of the MANE select protein

Interestingly R49* is created by a delins/2 missense in cis, 1 common R49Q and 1 rare R49W, some UNaffected family members just have the common missense without the other in cis.

Immunofluorescence studies in patient platelets showed a 50% reduction of APOLD1 and disrupted cytoskeletal and junctional organization.

SiRNA silencing of APOLD1 in HBDEC cells resulted in altered cell shape and size, and were associated with endothelial cell junction dismantling. These cells were also almost devoid of VWF.
Sources: Literature
Mendeliome v1.1587 ZSCAN10 Rylee Peters gene: ZSCAN10 was added
gene: ZSCAN10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZSCAN10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZSCAN10 were set to PMID: 38386308
Phenotypes for gene: ZSCAN10 were set to syndromic disease MONDO:0002254
Review for gene: ZSCAN10 was set to GREEN
Added comment: Bi-allelic ZSCAN10 loss-of-function variants were identified in seven affected individuals from five unrelated families with syndromic neurodevelopmental disorder.

Highly consistent phenotypic features include global developmental delay, behavioural abnormalities, and variable facial asymmetry with outer and inner ear malformations leading to profound SNHL.

Facial asymmetry was recapitulated in the Zscan10 mouse model along with inner and outer ear malformations.
Sources: Literature
Mendeliome v1.1587 SLC12A9 Zornitza Stark Marked gene: SLC12A9 as ready
Mendeliome v1.1587 SLC12A9 Zornitza Stark Gene: slc12a9 has been classified as Green List (High Evidence).
Mendeliome v1.1587 SLC12A9 Zornitza Stark Classified gene: SLC12A9 as Green List (high evidence)
Mendeliome v1.1587 SLC12A9 Zornitza Stark Gene: slc12a9 has been classified as Green List (High Evidence).
Mendeliome v1.1586 SNF8 Elena Savva Marked gene: SNF8 as ready
Mendeliome v1.1586 SNF8 Elena Savva Gene: snf8 has been classified as Green List (High Evidence).
Mendeliome v1.1586 SLC12A9 Zornitza Stark gene: SLC12A9 was added
gene: SLC12A9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC12A9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC12A9 were set to 38334070
Phenotypes for gene: SLC12A9 were set to Neurodevelopmental disorder, MONDO:0700092, SLC12A9-related
Review for gene: SLC12A9 was set to GREEN
Added comment: Three individuals from unrelated families with bi-allelic LoF variants and a neurodevelopment phenotype, skeletal and brain abnormalities, hypopigmentation, dysmorphic features.
Sources: Literature
Mendeliome v1.1586 SNF8 Elena Savva Classified gene: SNF8 as Green List (high evidence)
Mendeliome v1.1586 SNF8 Elena Savva Gene: snf8 has been classified as Green List (High Evidence).
Mendeliome v1.1585 SNF8 Chern Lim gene: SNF8 was added
gene: SNF8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SNF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNF8 were set to 38423010
Phenotypes for gene: SNF8 were set to Neurodevelopmental disorder (MONDO:0700092), SNF8-related
Review for gene: SNF8 was set to GREEN
gene: SNF8 was marked as current diagnostic
Added comment: PMID: 38423010
- Nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative features caused by bi-allelic variants in SNF8. In total, three putative LoF variants and four missense variants were identified.
- The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental arrest, and early death. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile) as compound heterozygous.
- Functional studies using fibroblasts derived from patients and zebrafish model showed LoF is the disease mech.
Sources: Literature
Mendeliome v1.1585 TUBA4A Seb Lunke Marked gene: TUBA4A as ready
Mendeliome v1.1585 TUBA4A Seb Lunke Gene: tuba4a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1585 TUBA4A Seb Lunke Classified gene: TUBA4A as Amber List (moderate evidence)
Mendeliome v1.1585 TUBA4A Seb Lunke Gene: tuba4a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1584 HSPG2 Dean Phelan reviewed gene: HSPG2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38424183; Phenotypes: Dyssegmental dysplasia, Rolland-Desbuquois type (MONDO:0009139); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1584 SNUPN Suliman Khan gene: SNUPN was added
gene: SNUPN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SNUPN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNUPN were set to PMID: 38413582; PMID: 38366623
Phenotypes for gene: SNUPN were set to autosomal recessive limb-girdle muscular dystrophy MONDO:0015152
Review for gene: SNUPN was set to GREEN
Added comment: PMID: 38413582: reported 18 children from 15 unrelated families with muscular phenotypes, including proximal upper limb weakness, distal upper and lower limb weakness, and myopathy (EMG) with elevated serum creatinine kinase level. Exome sequencing revealed nine hypomorphic biallelic variants in the SNUPN gene, predominantly clustered in the last coding exon. Functional studies showed that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients’ primary fibroblasts.

PMID: 38366623: reported five individuals from two unrelated families with limb-girdle muscular dystrophy.
Sources: Literature
Mendeliome v1.1584 APOLD1 Lucy Spencer gene: APOLD1 was added
gene: APOLD1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: APOLD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: APOLD1 were set to 35638551
Phenotypes for gene: APOLD1 were set to Bleeding disorder, vascular-type (MIM#620715)
Review for gene: APOLD1 was set to AMBER
Added comment: PMID: 35638551
1 family with an atypical inherited bleeding disorder characterised by severe spontaneous bleeding episodes in childhood and microcirculatory problems. 4 affected individuals across 2 generations have R49*in APOLD1, another affected individual from a third generation was not able to be sequenced = 4 meiosis. 4 unaffected individuals did not have the variant.

This gene has no NMD region, R49* would affect 82% of the protein. Paper is not using the MANE select transcript, alt p. in MANE select is R18* which affects 92% of the MANE select protein

Interestingly R49* is created by a delins/2 missense in cis, 1 common R49Q and 1 rare R49W, some UNaffected family members just have the common missense without the other in cis.

Immunofluorescence studies in patient platelets showed a 50% reduction of APOLD1 and disrupted cytoskeletal and junctional organization.
Sources: Literature
Mendeliome v1.1584 RGS6 Seb Lunke Marked gene: RGS6 as ready
Mendeliome v1.1584 RGS6 Seb Lunke Gene: rgs6 has been classified as Red List (Low Evidence).
Mendeliome v1.1584 RGS6 Seb Lunke gene: RGS6 was added
gene: RGS6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RGS6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RGS6 were set to 38332109; 25525169
Phenotypes for gene: RGS6 were set to Cataract,MONDO:0005129; intellectual disability, MONDO:0001071; microcephaly, MONDO:0001149
Review for gene: RGS6 was set to RED
Added comment: Original paper from 2015 describes single consanguineous with two siblings affected by cataract, developmental delay, and microcephaly >3SD. A homozygous canonical splice variant predicted to lead to NMD in RGS6 was identified by WGS and linkage (rather than full WGS analysis). The 2024 paper speculates that the phenotype is driven by a change in RGS6 isoform balance rather than LoF using a knock-out mouse model. It is noted that the mice did not have microcephaly, and ID was assessed using social interaction. No mention of cataract in the mice.
Sources: Literature
Mendeliome v1.1583 TOGARAM2 Naomi Baker gene: TOGARAM2 was added
gene: TOGARAM2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TOGARAM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOGARAM2 were set to PMID:38374469
Phenotypes for gene: TOGARAM2 were set to Nonsyndromic genetic hearing loss (MONDO:0019497), TOGARAM2-related
Review for gene: TOGARAM2 was set to RED
Added comment: Paper reports one individual with bilateral profound hearing loss with a homozygous TOGARAM2 nonsense variant and demonstrated reduced mRNA expression in transfected cells.
Sources: Literature
Mendeliome v1.1583 DIP2C Melanie Marty gene: DIP2C was added
gene: DIP2C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DIP2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DIP2C were set to PMID: 38421105
Phenotypes for gene: DIP2C were set to Neurodevelopmental disorder (MONDO#0700092), DIP2C-related
Review for gene: DIP2C was set to GREEN
Added comment: PMID: 38421105 - Twenty three patients with het DIP2C variants (10 de novo).
All patients had developmental delays affecting expressive language and speech, most had mild dev delay and ID. Four patients had seizures. Additional phenotypic findings were non-specific but recurrent anomalies did include a high anterior hair-line, prominent forehead, and a broad nasal tip. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects,and bicuspid aortic valve)
Sources: Literature
Mendeliome v1.1583 NIT1 Ain Roesley Marked gene: NIT1 as ready
Mendeliome v1.1583 NIT1 Ain Roesley Gene: nit1 has been classified as Green List (High Evidence).
Mendeliome v1.1583 NIT1 Zornitza Stark Marked gene: NIT1 as ready
Mendeliome v1.1583 NIT1 Zornitza Stark Gene: nit1 has been classified as Green List (High Evidence).
Mendeliome v1.1583 NIT1 Ain Roesley Classified gene: NIT1 as Green List (high evidence)
Mendeliome v1.1583 NIT1 Ain Roesley Gene: nit1 has been classified as Green List (High Evidence).
Mendeliome v1.1582 NIT1 Zornitza Stark Classified gene: NIT1 as Green List (high evidence)
Mendeliome v1.1582 NIT1 Zornitza Stark Gene: nit1 has been classified as Green List (High Evidence).
Mendeliome v1.1581 NIT1 Paul De Fazio edited their review of gene: NIT1: Changed rating: GREEN
Mendeliome v1.1581 TUBA4A Sarah Pantaleo gene: TUBA4A was added
gene: TUBA4A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TUBA4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TUBA4A were set to PMID: 38413182
Phenotypes for gene: TUBA4A were set to Congenital myopathy MONDO:0019952
Review for gene: TUBA4A was set to AMBER
Added comment: One novel TUBA4A variant in two unrelated Chinese patients with sporadic congenital myopathy.

Identified candidate genes using laser capture micro dissection, proteomics, WES, clinical data, myopathological changes, electrophysiological exams and thigh muscle MRIs.

The variant is de novo in both patients, c.679C>T, p.(Leu227Phe). The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiqution-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of Leu227Phe resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model.

Patient 1 is 14yo and had delayed motor development milestones since infancy. Myopathic face, high-arched palate, waddling gait, winged scapula and muscle weakness in four limbs with lower extremities and proximal muscle more severely affected. Follow up at 14yo showed slight improvement in motor function compared with 3yo.

Patient 2 is 6yo and presented with motor retardation since birth. At 3yo, presented with mild ptosis and ophthalmoparesis, high-arched palate and muscle weakness involving both proximal and distal in all limbs.

No likely pathogenic variants in 116 other protein-encoding genes. Variants confirmed by Sanger sequencing and absent from gnomAD. ACMG predicts likely pathogenic classification.
Sources: Literature
Mendeliome v1.1581 DENND5B Elena Savva Publications for gene: DENND5B were set to
Mendeliome v1.1580 NIT1 Paul De Fazio gene: NIT1 was added
gene: NIT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NIT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NIT1 were set to 38430071
Phenotypes for gene: NIT1 were set to Cerebrovascular disorder, NIT1-related (MONDO:0011057)
Penetrance for gene: NIT1 were set to unknown
gene: NIT1 was marked as current diagnostic
Added comment: 5 unrelated families reported with recessively inherited cerebral small vessel disease had compound hetereozygous or homozygous variants in NIT1. 1 family (3 siblings) had p.(Ala68*) in trans with p.(Arg243Trp), the remaining 4 families (1 individual each) were all homozygous for p.(Arg243Trp).

Patients presented in mid-adulthood with progressive movement disorders (e.g. dystonia, chorea, bradykinesia and tremor, gait disturbance, dysarthria) and had abnormal brain MRI findings (honeycomb appearance of the basal ganglia-thalamus complex, due to numerous strongly dilated PVS). 3 patients had non-lobar intracerebral hemorrhage. Slowly progressive cognitive decline was also a key feature.

Metabolic analysis in urine confirmed loss of NIT1 enzymatic function.

Note p.(Arg243Trp) has 1 homozygote in gnomAD v4, but permitted due to later presentation in reported patients.
Sources: Literature
Mendeliome v1.1580 DENND5B Elena Savva reviewed gene: DENND5B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38387458; Phenotypes: Neurodevelopmental disorder (MONDO#0700092), DENND5B-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.1580 FEZF2 Ain Roesley Marked gene: FEZF2 as ready
Mendeliome v1.1580 FEZF2 Ain Roesley Gene: fezf2 has been classified as Green List (High Evidence).
Mendeliome v1.1580 RREB1 Zornitza Stark Publications for gene: RREB1 were set to 32938917
Mendeliome v1.1580 FEZF2 Ain Roesley Classified gene: FEZF2 as Green List (high evidence)
Mendeliome v1.1580 FEZF2 Ain Roesley Gene: fezf2 has been classified as Green List (High Evidence).
Mendeliome v1.1579 RREB1 Zornitza Stark Classified gene: RREB1 as Amber List (moderate evidence)
Mendeliome v1.1579 RREB1 Zornitza Stark Gene: rreb1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1578 RREB1 Zornitza Stark edited their review of gene: RREB1: Added comment: PMID 38332451: de novo LoF variant in an individual with phenotype consistent with the previous reports.; Changed rating: AMBER; Changed publications: 32938917, 38332451; Changed phenotypes: Rasopathy, MONDO:0021060, RREB1-related
Mendeliome v1.1578 FEZF2 Ain Roesley gene: FEZF2 was added
gene: FEZF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FEZF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FEZF2 were set to 38425142
Phenotypes for gene: FEZF2 were set to neurodevelopmental disorder MONDO:0700092, FEZF2-related
Review for gene: FEZF2 was set to GREEN
gene: FEZF2 was marked as current diagnostic
Added comment: - 7 indiv but 1 has whole gene deletion and 6x SNV (4x PTCs and 2x same missense Arg344Cys)
- of the 6x SNV, 4x de novo + 1x from affected father
- all have ID/ASD
- 1x seizures
- 1x hypotonia
- 1x motor coordination disorder
- 2x enuresis after 7yo
Sources: Literature
Mendeliome v1.1577 ZFX Zornitza Stark Marked gene: ZFX as ready
Mendeliome v1.1577 ZFX Zornitza Stark Gene: zfx has been classified as Green List (High Evidence).
Mendeliome v1.1577 ZFX Zornitza Stark Classified gene: ZFX as Green List (high evidence)
Mendeliome v1.1577 ZFX Zornitza Stark Gene: zfx has been classified as Green List (High Evidence).
Mendeliome v1.1576 ZFX Zornitza Stark gene: ZFX was added
gene: ZFX was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZFX was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: ZFX were set to 26350204; 26740508; 38325380
Phenotypes for gene: ZFX were set to Neurodevelopmental disorder, MONDO:0700092, ZFX-related
Review for gene: ZFX was set to GREEN
Added comment: A single ZFX variant has been associated with a neurodevelopmental disorder, that has a Rett syndrome-like phenotype disorder, in a 14 year old male. The ZFX variant was allelic with another X-linked variant in SHROOM4. These variants were inherited from the mother, who had random X inactivation pattern (PMID: 26740508).
PMID: 38325380 reports 11 ZFX variants in 18 subjects from 16 unrelated families (14 males and 4 females) with an X-linked neurodevelopmental disorder with recurrent facial gestalt. Seven variants were truncating and the remaining were missense variants within the Zinc finger array. In the pedigree of family 6 (figure 3, PMID: 38325380), it was apparent that there were female carriers of the ZFX variant (GRCh38 chrX: 24229396A>G, c.2438A>G, p.Tyr774Cys) with hyperparathyroidism and two affected males and one affected female, with the neurodevelopmental disorder. It appeared that skewed X-inactivation in the female carriers was responsible for the different phenotypic features. The association between ZFX variants and a novel neurodevelopmental disorder, was further supported by functional studies showing altered transcriptional activity in missense variants and altered behavior in a zebrafish loss-of-function model.
Sources: Literature
Mendeliome v1.1575 NARS Zornitza Stark commented on gene: NARS: AR disorder: assessed as LIMITED by ClinGen (borderline MODERATE).
Mendeliome v1.1575 STX4 Zornitza Stark Phenotypes for gene: STX4 were changed from Non-syndromic genetic hearing loss, MONDO:0019497, STX4-related. to Deafness, autosomal recessive 123, MIM# 620745
Mendeliome v1.1574 DES Zornitza Stark Mode of inheritance for gene: DES was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1573 PI4K2A Zornitza Stark Phenotypes for gene: PI4K2A were changed from complex neurodevelopmental disorder with motor features, PI4K2A-related, MONDO:0100516; Cutis laxa, intellectual disability, movement disorder to Neurodevelopmental disorder with hyperkinetic movements, seizures and structural brain abnormalities, MIM# 620732; Cutis laxa, intellectual disability, movement disorder
Mendeliome v1.1572 KLF14 Bryony Thompson Marked gene: KLF14 as ready
Mendeliome v1.1572 KLF14 Bryony Thompson Gene: klf14 has been classified as Red List (Low Evidence).
Mendeliome v1.1572 KLF14 Bryony Thompson Classified gene: KLF14 as Red List (low evidence)
Mendeliome v1.1572 KLF14 Bryony Thompson Gene: klf14 has been classified as Red List (Low Evidence).
Mendeliome v1.1571 NOTCH2NL Bryony Thompson Tag STR tag was added to gene: NOTCH2NL.
Mendeliome v1.1571 NLRP12 Bryony Thompson Publications for gene: NLRP12 were set to 18230725; 21360512; 24064030; 27633793
Mendeliome v1.1570 PCSK2 Bryony Thompson Classified gene: PCSK2 as Red List (low evidence)
Mendeliome v1.1570 PCSK2 Bryony Thompson Gene: pcsk2 has been classified as Red List (Low Evidence).
Mendeliome v1.1569 RFX6 Bryony Thompson Added comment: Comment on mode of inheritance: Mitchell-Riley syndrome is AR and MODY is AD
Mendeliome v1.1569 RFX6 Bryony Thompson Mode of inheritance for gene: RFX6 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.1568 PPP2R2B Bryony Thompson Tag STR tag was added to gene: PPP2R2B.
Mendeliome v1.1568 SAMD12 Bryony Thompson Tag STR tag was added to gene: SAMD12.
Mendeliome v1.1568 APPL1 Bryony Thompson Publications for gene: APPL1 were set to 26073777
Mendeliome v1.1567 APPL1 Bryony Thompson Classified gene: APPL1 as Red List (low evidence)
Mendeliome v1.1567 APPL1 Bryony Thompson Gene: appl1 has been classified as Red List (Low Evidence).
Mendeliome v1.1566 APPL1 Bryony Thompson Deleted their comment
Mendeliome v1.1566 APPL1 Bryony Thompson edited their review of gene: APPL1: Added comment: PMID: 36208030 - a study using the UK Biobank comparing individuals with and without diabetes found LoF variants in APPL1 were ‘Inconsistent’ with being high penetrant for diabetes (failed both statistical criteria - enrichment & comparison to maximum credible allele frequency). Refutes previous study.; Changed rating: RED; Changed publications: 26073777, 36208030
Mendeliome v1.1566 KLF11 Bryony Thompson Publications for gene: KLF11 were set to 15774581; 26248217; 23589285; 31124255
Mendeliome v1.1565 KLF11 Bryony Thompson Classified gene: KLF11 as Red List (low evidence)
Mendeliome v1.1565 KLF11 Bryony Thompson Added comment: Comment on list classification: Association with monogenic diabetes now Refuted
Classification - 02/08/2023. ClinGen Monogenic Diabetes GCEP - https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b1e38a49-7c12-4514-a2a1-109e04da146f-2023-02-08T170000.000Z?page=1&size=25&search=
Mendeliome v1.1565 KLF11 Bryony Thompson Gene: klf11 has been classified as Red List (Low Evidence).
Mendeliome v1.1564 KLF14 Hali Van Niel changed review comment from: PMID: 33389382
Case-sibling study of 92 healthy individuals and 92 type 2 diabetes patients found KLF14 SNPs associated with susceptibility to type 2 diabetes

PMID: 35081256
Large scale association analysis found type 2 susceptibility of KLF14 SNPS appearing to be driven by reduced insulin sensitivity

PMID: 24486580
Global Meta-analysis found risk allele SNP associated with increased risk of type 2 diabetes (in global population)
Sources: Other; to: Cannot find any evidence of association with mendelian disease

PMID: 33389382
Case-sibling study of 92 healthy individuals and 92 type 2 diabetes patients found KLF14 SNPs associated with susceptibility to type 2 diabetes

PMID: 35081256
Large scale association analysis found type 2 susceptibility of KLF14 SNPS appearing to be driven by reduced insulin sensitivity

PMID: 24486580
Global Meta-analysis found risk allele SNP associated with increased risk of type 2 diabetes (in global population)
Sources: Other
Mendeliome v1.1564 KLF14 Hali Van Niel gene: KLF14 was added
gene: KLF14 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: KLF14 was set to Unknown
Publications for gene: KLF14 were set to 33389382; 35081256; 24486580
Phenotypes for gene: KLF14 were set to diabetes mellitus MONDO:0005015
Review for gene: KLF14 was set to RED
Added comment: PMID: 33389382
Case-sibling study of 92 healthy individuals and 92 type 2 diabetes patients found KLF14 SNPs associated with susceptibility to type 2 diabetes

PMID: 35081256
Large scale association analysis found type 2 susceptibility of KLF14 SNPS appearing to be driven by reduced insulin sensitivity

PMID: 24486580
Global Meta-analysis found risk allele SNP associated with increased risk of type 2 diabetes (in global population)
Sources: Other
Mendeliome v1.1564 PCSK2 Hali Van Niel gene: PCSK2 was added
gene: PCSK2 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: PCSK2 was set to Unknown
Publications for gene: PCSK2 were set to 26607656; 7698505; 17618154
Phenotypes for gene: PCSK2 were set to diabetes mellitus MONDO:0005015
Review for gene: PCSK2 was set to RED
Added comment: Cannot find any evidence of association with mendelian disease

PMID: 26607656

10 SNPs genotyped, genetic polymorphisms responsible for glucose homeostasis and incidental diabetes

PMID: 7698505
DNA polymorphism found in 11% of non insulin dependent diabetes patients (out of 152 japanese patients) vs 4% in health population (out of 102 japanese patients).

PMID: 17618154
29 SNPS analysed across PCSK2, 4 SNPS associated type 2 diabetes in african american population
Sources: Other
Mendeliome v1.1564 ACO2 Zornitza Stark Publications for gene: ACO2 were set to 22405087; 25351951; 30689204; 32519519; 25351951
Mendeliome v1.1563 ACO2 Zornitza Stark Mode of inheritance for gene: ACO2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.1562 YEATS2 Zornitza Stark Tag STR tag was added to gene: YEATS2.
Mendeliome v1.1562 YEATS2 Elena Savva Marked gene: YEATS2 as ready
Mendeliome v1.1562 YEATS2 Elena Savva Gene: yeats2 has been classified as Red List (Low Evidence).
Mendeliome v1.1562 YEATS2 Elena Savva gene: YEATS2 was added
gene: YEATS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: YEATS2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: YEATS2 were set to PMID: 22713812; 31539032
Phenotypes for gene: YEATS2 were set to ?Epilepsy, myoclonic, familial adult, 4 MIM#615127
Review for gene: YEATS2 was set to RED
Added comment: PMID: 22713812 - 13 members of a single family with Benign Adult Familial Myoclonic Epilepsy (BAFME). The average age of onset was 19.5 (range 10–33) years for tremor and 25 (range 19–33) years for seizures.
PMID: 31539032 - Expansions of TTTTA and insertions of TTTCA repeats in intron 1 of YEATS2 segregated in the same family ^.
Sources: Literature
Mendeliome v1.1561 WASHC4 Elena Savva Phenotypes for gene: WASHC4 were changed from Mental retardation, autosomal recessive 43, MIM #615817 to Intellectual developmental disorder, autosomal recessive 43 MIM#615817
Mendeliome v1.1560 UGGT1 Elena Savva Marked gene: UGGT1 as ready
Mendeliome v1.1560 UGGT1 Elena Savva Gene: uggt1 has been classified as Red List (Low Evidence).
Mendeliome v1.1560 UGGT1 Elena Savva gene: UGGT1 was added
gene: UGGT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: UGGT1 was set to Unknown
Review for gene: UGGT1 was set to RED
Added comment: Gene was on the Oliver list for epilepsy genes.

No gene-disease association paper has been published.

GnomAD NOT constrained for LOF variants.
Sources: Literature
Mendeliome v1.1559 FZD5 Zornitza Stark Phenotypes for gene: FZD5 were changed from Coloboma MONDO:0001476 to Microphthalmia/coloboma 11, MIM# 620731
Mendeliome v1.1558 FZD5 Zornitza Stark edited their review of gene: FZD5: Changed phenotypes: Microphthalmia/coloboma 11, MIM# 620731
Mendeliome v1.1558 STAB1 Zornitza Stark Phenotypes for gene: STAB1 were changed from Iron metabolism disease (MONDO:0002279), STAB1-related to Hyperferritinemia, MIM# 620729
Mendeliome v1.1557 STAB1 Zornitza Stark reviewed gene: STAB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperferritinemia, MIM# 620729; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1557 PUM1 Zornitza Stark Phenotypes for gene: PUM1 were changed from Spinocerebellar ataxia 47, MIM# 617931; Neurodevelopmental disorder, MONDO:0700092, PUM1-related to Spinocerebellar ataxia 47, MIM# 617931; Neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism, MIM# 620719
Mendeliome v1.1556 PUM1 Zornitza Stark Publications for gene: PUM1 were set to 29474920; 25768905; 30903679; 31859446
Mendeliome v1.1555 PUM1 Zornitza Stark edited their review of gene: PUM1: Changed phenotypes: Spinocerebellar ataxia 47, MIM# 617931, Neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism, MIM# 620719
Mendeliome v1.1555 ACO2 Rylee Peters reviewed gene: ACO2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34056600; Phenotypes: Optic atrophy 9, MIM# 616289; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.1555 TRMT1 Elena Savva Phenotypes for gene: TRMT1 were changed from Mental retardation, autosomal recessive 68; OMIM #618302 to Intellectual developmental disorder, autosomal recessive 68 MIM#618302
Mendeliome v1.1554 NEK1 Zornitza Stark Phenotypes for gene: NEK1 were changed from Short-rib thoracic dysplasia 6 with or without polydactyly, MIM# 263520; Amyotrophic lateral sclerosis, susceptibility to, 24, MIM# 617892 to Short-rib thoracic dysplasia 6 with or without polydactyly, MIM# 263520; Orofaciodigital syndrome II , MIM# 252100; Amyotrophic lateral sclerosis, susceptibility to, 24, MIM# 617892
Mendeliome v1.1553 NEK1 Zornitza Stark Publications for gene: NEK1 were set to 21211617; 22499340; 25492405; 28123176; 33445179
Mendeliome v1.1552 NEK1 Zornitza Stark edited their review of gene: NEK1: Added comment: PMID 27530628: two brothers with OFD phenotype.; Changed publications: 21211617, 22499340, 25492405, 28123176, 27530628; Changed phenotypes: Short-rib thoracic dysplasia 6 with or without polydactyly, MIM# 263520, Orofaciodigital syndrome II , MIM# 252100, Amyotrophic lateral sclerosis, susceptibility to, 24, MIM# 617892
Mendeliome v1.1552 HMBS Zornitza Stark Phenotypes for gene: HMBS were changed from Porphyria, acute intermittent, MIM#176000; Porphyria, acute intermittent, non-erythroid variant, MIM#176000 to Porphyria, acute intermittent, MIM#176000; Porphyria, acute intermittent, non-erythroid variant, MIM#176000; Encephalopathy, porphyria-related MIM#620704; Leukoencephalopathy, porphyria-related, MIM#620711
Mendeliome v1.1551 HMBS Zornitza Stark edited their review of gene: HMBS: Changed phenotypes: Porphyria, acute intermittent, MIM#176000, Porphyria, acute intermittent, non-erythroid variant, MIM#176000, Encephalopathy, porphyria-related MIM#620704, Leukoencephalopathy, porphyria-related, MIM#620711
Mendeliome v1.1551 LCP2 Achchuthan Shanmugasundram reviewed gene: LCP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37211057; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1551 MYO3A Zornitza Stark Phenotypes for gene: MYO3A were changed from Deafness, autosomal recessive 30 OMIM:607101; autosomal recessive nonsyndromic deafness 30 MONDO:0011774; dominant deafness to Deafness, autosomal recessive 30, MIM# 607101; Deafness, autosomal dominant 90, MIM# 620722
Mendeliome v1.1550 MYO3A Zornitza Stark edited their review of gene: MYO3A: Changed phenotypes: Deafness, autosomal recessive 30, MIM# 607101, Deafness, autosomal dominant 90, MIM# 620722
Mendeliome v1.1550 TMTC2 Zornitza Stark Phenotypes for gene: TMTC2 were changed from Deafness to Deafness, autosomal recessive 122, MIM# 620714
Mendeliome v1.1549 TMTC2 Zornitza Stark Publications for gene: TMTC2 were set to 29671961; 27311106
Mendeliome v1.1548 TMTC2 Zornitza Stark Mode of inheritance for gene: TMTC2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1547 TMTC2 Zornitza Stark edited their review of gene: TMTC2: Added comment: Single family reported with bi-allelic variants.

Mouse model.; Changed publications: 29671961, 27311106, 37943620, 30188326; Changed phenotypes: Deafness, autosomal recessive 122, MIM# 620714; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1547 TMLHE Bryony Thompson Classified gene: TMLHE as Red List (low evidence)
Mendeliome v1.1547 TMLHE Bryony Thompson Added comment: Comment on list classification: ClinGen Disputed gene-disease association Classification - 03/02/2021 by ID & Autism GCEP: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7a780ea6-ad4e-417a-a596-27188e327aad-2021-03-02T050000.000Z?page=1&size=25&search=
Mendeliome v1.1547 TMLHE Bryony Thompson Gene: tmlhe has been classified as Red List (Low Evidence).
Mendeliome v1.1546 ANKZF1 Zornitza Stark reviewed gene: ANKZF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28302725, 36857589; Phenotypes: Infantile-onset inflammatory bowel disease, MONDO:0005265, ANKZF1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1546 CARD8 Zornitza Stark Classified gene: CARD8 as Amber List (moderate evidence)
Mendeliome v1.1546 CARD8 Zornitza Stark Gene: card8 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1545 CARD8 Zornitza Stark edited their review of gene: CARD8: Added comment: Additional individual reported with JRA and IBD.; Changed rating: AMBER; Changed publications: 29408806, 37724393
Mendeliome v1.1545 RAB34 Zornitza Stark Phenotypes for gene: RAB34 were changed from Multiple congenital anomalies, (MONDO:0019042), RAB34-related to Orofaciodigital syndrome 20, MIM#620718
Mendeliome v1.1544 ONECUT1 Bryony Thompson Marked gene: ONECUT1 as ready
Mendeliome v1.1544 ONECUT1 Bryony Thompson Gene: onecut1 has been classified as Green List (High Evidence).
Mendeliome v1.1544 ONECUT1 Bryony Thompson Classified gene: ONECUT1 as Green List (high evidence)
Mendeliome v1.1544 ONECUT1 Bryony Thompson Gene: onecut1 has been classified as Green List (High Evidence).
Mendeliome v1.1543 ONECUT1 Bryony Thompson gene: ONECUT1 was added
gene: ONECUT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ONECUT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ONECUT1 were set to 37639628; 34663987; 10825208
Phenotypes for gene: ONECUT1 were set to Neonatal diabetes mellitus MONDO:0016391
Review for gene: ONECUT1 was set to GREEN
Added comment: 3 unrelated neonatal diabetes cases with homozygous variants & supporting iPSC/mouse models
PMID: 37639628 - UK biobank study of ONECUT1 variants in neonatal diabetes mellitus (NDM), MODY, and type 2 diabetes. Identified a case with syndromic NDM with a homozygous frameshift (p.Met289Argfs*8). Rare heterozygous variants were not enriched in individuals with suspected MODY (n=484). Heterozygous null variants were significantly associated with type 2 diabetes (p=0.006) as a potential susceptibility gene.

PMID: 34663987 - 2 consanguineous families with homozygous variants (Glu231Ter or Glu231Asp) in cases with syndromic ND. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation.

PMID: 10825208 - Hnf6 (old gene name) null mice have diabetes
Sources: Literature
Mendeliome v1.1542 HSPA1L Zornitza Stark Marked gene: HSPA1L as ready
Mendeliome v1.1542 HSPA1L Zornitza Stark Gene: hspa1l has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1542 HSPA1L Zornitza Stark Classified gene: HSPA1L as Amber List (moderate evidence)
Mendeliome v1.1542 HSPA1L Zornitza Stark Gene: hspa1l has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1541 HSPA1L Zornitza Stark reviewed gene: HSPA1L: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: inflammatory bowel disease, MONDO:0005265; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1541 SCGN Zornitza Stark Marked gene: SCGN as ready
Mendeliome v1.1541 SCGN Zornitza Stark Gene: scgn has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1541 SCGN Zornitza Stark Classified gene: SCGN as Amber List (moderate evidence)
Mendeliome v1.1541 SCGN Zornitza Stark Gene: scgn has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1540 SIRT1 Zornitza Stark Marked gene: SIRT1 as ready
Mendeliome v1.1540 SIRT1 Zornitza Stark Gene: sirt1 has been classified as Red List (Low Evidence).
Mendeliome v1.1540 SIRT1 Zornitza Stark Classified gene: SIRT1 as Red List (low evidence)
Mendeliome v1.1540 SIRT1 Zornitza Stark Gene: sirt1 has been classified as Red List (Low Evidence).
Mendeliome v1.1539 TNRC6A Elena Savva Marked gene: TNRC6A as ready
Mendeliome v1.1539 TNRC6A Elena Savva Gene: tnrc6a has been classified as Red List (Low Evidence).
Mendeliome v1.1539 TNRC6A Elena Savva gene: TNRC6A was added
gene: TNRC6A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TNRC6A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TNRC6A were set to PMID: 29507423; 33040085
Phenotypes for gene: TNRC6A were set to ?Epilepsy, familial adult myoclonic, 6 MIM#618074
Review for gene: TNRC6A was set to RED
Added comment: PMID: 29507423;33040085 - intronic expansion in a cohort with familial myoclonic epilepsy, also observed in controls but enriched in the affect cohort.

Gene was listed in the Oliver list
Sources: Literature
Mendeliome v1.1538 FBXO31 Lucy Spencer reviewed gene: FBXO31: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal recessive 45 (MIM#615979); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1538 SIRT1 Achchuthan Shanmugasundram gene: SIRT1 was added
gene: SIRT1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SIRT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SIRT1 were set to 23473037
Phenotypes for gene: SIRT1 were set to autoimmune disease, MONDO:0007179
Review for gene: SIRT1 was set to RED
Added comment: PMID:23473037 reported the identification of a missense SIRT1 variant (p.Leu107Pro) in five members of a single family and all five of them had autoimmune disorder, four had type I diabetes and one had ulcerative colitis.
Sources: Literature
Mendeliome v1.1538 SCGN Achchuthan Shanmugasundram gene: SCGN was added
gene: SCGN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SCGN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCGN were set to 31663849
Phenotypes for gene: SCGN were set to ulcerative colitis, MONDO:0005101
Review for gene: SCGN was set to AMBER
Added comment: PMID:31663849 reported three siblings with homozygous missense SCGN variant and with early-onset ulcerative colitis. Functional studies demonstrated that SCGN variant identified impacted the localisation of the SNARE complex partner, SNAP25, leading to impaired hormone release. In addition, SCGN knockout mouse model recapitulated impaired hormone release and susceptibility to DSS-induced colitis.
Sources: Literature
Mendeliome v1.1538 HSPA1L Achchuthan Shanmugasundram gene: HSPA1L was added
gene: HSPA1L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HSPA1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HSPA1L were set to 28126021
Phenotypes for gene: HSPA1L were set to inflammatory bowel disease, MONDO:0005265
Review for gene: HSPA1L was set to GREEN
Added comment: PMID:28126021 reported the identification of a heterozygous de novo variant (p.Ser277Leu) in HSPA1L in a patient with inflammatory bowel disease. In addition, five additional rare HSPA1L variants (p.Gly77Ser, p.Leu172del, p.Thr267Ile, p.Ala268Thr, p.Glu558Asp) were identified in six patients from a cohort of 136 IBD patients with WES data.

Functional studies showed that all six HSPA1L variant proteins showed decreased chaperone activity in vitro. Moreover, three variants demonstrated dominant negative effects on HSPA1L and HSPA1A protein activity.
Sources: Literature
Mendeliome v1.1538 TET3 Elena Savva Phenotypes for gene: TET3 were changed from Intellectual disability; dysmorphic features; abnormal growth; movement disorders to Beck-Fahrner syndrome MIM#618798
Mendeliome v1.1537 PRDM8 Zornitza Stark Marked gene: PRDM8 as ready
Mendeliome v1.1537 PRDM8 Zornitza Stark Gene: prdm8 has been classified as Red List (Low Evidence).
Mendeliome v1.1537 PRDM8 Zornitza Stark gene: PRDM8 was added
gene: PRDM8 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PRDM8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM8 were set to 2296154; 35034233
Phenotypes for gene: PRDM8 were set to Epilepsy, progressive myoclonic, 10 MIM#616640
Review for gene: PRDM8 was set to RED
Added comment: - PMID:22961547, 3 individuals from one family, all with myoclonic epilepsy, all had the Phe261Leu variant. This variant is absent from gnomAD V4.
- PMID: 35034233, Two individuals from one family, no clinical seizures but presented with myoclonus and abnormal EEG (generalised epileptiform charges), these individuals had the Ala230Gly missense change, which has currently been reported as a VUS.
Sources: Expert list
Mendeliome v1.1536 PRIMA1 Zornitza Stark Marked gene: PRIMA1 as ready
Mendeliome v1.1536 PRIMA1 Zornitza Stark Gene: prima1 has been classified as Red List (Low Evidence).
Mendeliome v1.1536 PRIMA1 Zornitza Stark gene: PRIMA1 was added
gene: PRIMA1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PRIMA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRIMA1 were set to 26339676
Phenotypes for gene: PRIMA1 were set to Frontal Lobe Epilepsy MONDO:0002612
Review for gene: PRIMA1 was set to RED
Added comment: - 2/3 siblings from unaffected parents in PMID: 26339676 were diagnosed with nocturnal frontal lobe epilepsy, which was confirmed by EEG. The affected siblings were homozygous for the c.93+2T>C variant canonical splice site variant. This variant was demonstrated by mini-gene assay to skip exon 2 of PRIMA1. Overall 1 family, 2 individuals with epilepsy and high impact variants in PRIMA1.
Sources: Expert list
Mendeliome v1.1535 MAX Zornitza Stark Phenotypes for gene: MAX were changed from {Pheochromocytoma, susceptibility to}, MIM# 171300; Syndromic disease (MONDO:0002254), MAX-related to {Pheochromocytoma, susceptibility to}, MIM# 171300; Polydactyly-macrocephaly syndrome, MIM# 620712
Mendeliome v1.1534 PLXNC1 Zornitza Stark Marked gene: PLXNC1 as ready
Mendeliome v1.1534 PLXNC1 Zornitza Stark Gene: plxnc1 has been classified as Red List (Low Evidence).
Mendeliome v1.1534 PLXNC1 Zornitza Stark gene: PLXNC1 was added
gene: PLXNC1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PLXNC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLXNC1 were set to 36808730
Phenotypes for gene: PLXNC1 were set to Malformations of cortical development
Review for gene: PLXNC1 was set to RED
Added comment: This gene was included in the genes4epilepsy resource (PMID:36808730) and was reported as being associated with the clinical phenotype "malformations of cortical development". There are no current PubMed articles linking this gene with epilepsy however
Sources: Expert list
Mendeliome v1.1533 CASZ1 Zornitza Stark Marked gene: CASZ1 as ready
Mendeliome v1.1533 CASZ1 Zornitza Stark Gene: casz1 has been classified as Green List (High Evidence).
Mendeliome v1.1533 CASZ1 Zornitza Stark Classified gene: CASZ1 as Green List (high evidence)
Mendeliome v1.1533 CASZ1 Zornitza Stark Gene: casz1 has been classified as Green List (High Evidence).
Mendeliome v1.1532 CASZ1 Zornitza Stark gene: CASZ1 was added
gene: CASZ1 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: CASZ1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CASZ1 were set to 28099117; 36293425; 31268246
Phenotypes for gene: CASZ1 were set to Dilated cardiomyopathy, MONDO:0005021, CASZ1-related; left ventricular non compaction
Review for gene: CASZ1 was set to GREEN
Added comment: Rare cause of paeditric onsent DCM. at least 3 papers report LoF variants, 2 of which each report a novel de novo frameshift variant in children diagnosed with DCM less than 1 and who died at 11 mths ( PMID: 31268246; Guo 2019) and 22mths (PMID: 36293425, Orlova 2022). Another paper (PMID: 28099117, Qiu 2017) reported a nonsense variant that segregated with DCM in a family in an AD fashion (full text not available).
Sources: Expert list
Mendeliome v1.1531 SMC3 Zornitza Stark Publications for gene: SMC3 were set to 18996922; 25655089; 31334757
Mendeliome v1.1530 NDUFB9 Zornitza Stark Publications for gene: NDUFB9 were set to 22200994
Mendeliome v1.1529 NDUFB9 Zornitza Stark edited their review of gene: NDUFB9: Added comment: PMID: 38129218: Thr144Met, listed as ACMG-P, hom in 1x pt with mito complex I deficiency and leukodystrophy, no functional studies, both parents are het.

However, this variant has 2 homozygotes in gnomADv4 so unlikely pathogenic.; Changed publications: 22200994, 38129218
Mendeliome v1.1529 DNM2 Bryony Thompson reviewed gene: DNM2: Rating: RED; Mode of pathogenicity: None; Publications: 23092955; Phenotypes: fetal akinesia-cerebral and retinal hemorrhage syndrome MONDO:0014149; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1529 TAF1C Elena Savva Phenotypes for gene: TAF1C were changed from Global developmental delay; Intellectual disability; Spasticity; Strabismus; Seizures; Abnormality of nervous system morphology to Neurodevelopmental disorder (MONDO#0700092), TAF1C-related
Mendeliome v1.1528 SMC3 Bryony Thompson reviewed gene: SMC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 38297832; Phenotypes: Cornelia de Lange syndrome MONDO:0016033; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1528 BET1 Zornitza Stark Phenotypes for gene: BET1 were changed from Muscular dystrophy, MONDO:0019950, BET1-related; Epilepsy to Muscular dystrophy, congenital, with rapid progression, MIM# 254100
Mendeliome v1.1527 BET1 Zornitza Stark edited their review of gene: BET1: Changed phenotypes: Muscular dystrophy, congenital, with rapid progression, MIM# 254100
Mendeliome v1.1527 CSTF2 Zornitza Stark Phenotypes for gene: CSTF2 were changed from Intellectual disability to Intellectual developmental disorder, X-linked 113, MIM# 301116
Mendeliome v1.1526 CSTF2 Zornitza Stark edited their review of gene: CSTF2: Changed phenotypes: Intellectual developmental disorder, X-linked 113, MIM# 301116
Mendeliome v1.1526 TTR Zornitza Stark Tag treatable tag was added to gene: TTR.
Mendeliome v1.1526 DLG5 Zornitza Stark Phenotypes for gene: DLG5 were changed from Ciliopathy, MONDO:0016044, DLG5-related; Cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations to Yuksel-Vogel-Bauer syndrome, MIM#620703
Mendeliome v1.1525 DLG5 Zornitza Stark edited their review of gene: DLG5: Changed phenotypes: Yuksel-Vogel-Bauer syndrome, MIM#620703
Mendeliome v1.1525 DLG5 Zornitza Stark changed review comment from: Four unrelated families reported, supportive Xenopus animal model data.
Sources: Literature; to: Four unrelated families reported, supportive Xenopus animal model data. Cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations.
Sources: Literature
Mendeliome v1.1525 ASCC3 Zornitza Stark Phenotypes for gene: ASCC3 were changed from Neuromuscular syndrome; congenital myopathy to Intellectual developmental disorder, autosomal recessive 81, MIM# 620700
Mendeliome v1.1524 ASCC3 Zornitza Stark Publications for gene: ASCC3 were set to 21937992; https://doi.org/10.1016/j.xhgg.2021.100024
Mendeliome v1.1523 ASCC3 Zornitza Stark reviewed gene: ASCC3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal recessive 81, MIM# 620700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1523 GIGYF1 Zornitza Stark Phenotypes for gene: GIGYF1 were changed from Autism, Intellectual disability, GIGYF1-related (MONDO#0001071) to Autism spectrum disorder (MONDO:0005258), GIGYF1-related
Mendeliome v1.1522 HNRNPC Zornitza Stark Phenotypes for gene: HNRNPC were changed from Neurodevelopmental disorder (MONDO:0700092), HNRNPC-related to Intellectual developmental disorder-74, MIM#620688
Mendeliome v1.1521 HNRNPC Zornitza Stark edited their review of gene: HNRNPC: Changed phenotypes: intellectual developmental disorder-74, MIM#620688
Mendeliome v1.1521 RIC1 Zornitza Stark Phenotypes for gene: RIC1 were changed from Cleft lip; cataract; tooth abnormality; intellectual disability; facial dysmorphism; ADHD to Cleft lip/palate MONDO:0016044, RIC1-related; Cleft lip; cataract; tooth abnormality; intellectual disability; facial dysmorphism; ADHD
Mendeliome v1.1520 RIC1 Zornitza Stark Publications for gene: RIC1 were set to 31932796
Mendeliome v1.1519 RIC1 Zornitza Stark Mode of inheritance for gene: RIC1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1518 RIC1 Zornitza Stark Classified gene: RIC1 as Green List (high evidence)
Mendeliome v1.1518 RIC1 Zornitza Stark Gene: ric1 has been classified as Green List (High Evidence).
Mendeliome v1.1517 ACACA Zornitza Stark Classified gene: ACACA as Amber List (moderate evidence)
Mendeliome v1.1517 ACACA Zornitza Stark Gene: acaca has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1516 ACACA Zornitza Stark reviewed gene: ACACA: Rating: AMBER; Mode of pathogenicity: None; Publications: 36709796; Phenotypes: Acetyl-CoA carboxylase deficiency, MIM# 613933; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1516 ANO1 Zornitza Stark Phenotypes for gene: ANO1 were changed from Intestinal dysmotility syndrome, MIM# 620045; Moyamoya disease, MONDO:0016820, ANO1 related to Intestinal dysmotility syndrome, MIM# 620045; Moyamoya disease 7, MIM# 620687
Mendeliome v1.1515 ANO1 Zornitza Stark edited their review of gene: ANO1: Changed phenotypes: Intestinal dysmotility syndrome, MIM# 620045, Moyamoya disease 7, MIM# 620687
Mendeliome v1.1515 NUP160 Zornitza Stark Publications for gene: NUP160 were set to 30179222
Mendeliome v1.1514 NUP160 Zornitza Stark Classified gene: NUP160 as Green List (high evidence)
Mendeliome v1.1514 NUP160 Zornitza Stark Gene: nup160 has been classified as Green List (High Evidence).
Mendeliome v1.1513 NUP160 Melanie Marty changed review comment from: PMID: 30910934 1 x patient with familial steroid-resistant nephrotic syndrome (SRNS) and FSGS carried novel compound-heterozygous variants in NUP160 (R1173X and E803K). Silencing of Drosophila NUP160 specifically in nephrocytes (fly renal cells) led to functional abnormalities, reduced cell size and nuclear volume, and disorganized nuclear membrane structure. These defects were completely rescued by the expression of the wild-type human NUP160 gene in nephrocytes.

PMID: 30179222 1 x family (2 sibs) with compound het variants E803K and Arg910X. 1 Sib had SRNS and FSGS, the other had proteinuria.

PMID: 33456446 1 x family (2 sibs) with steroid-resistant nephrotic syndrome and chronic kidney disease. Homozygous for NUP160 c.1179+5G>A, confirmed by RT-PCR to cause abnormal splicing [r.1102_1179del;p.(Phe368_Gln393del)]. These individuals also had additional neurological features of intellectual disability and epilepsy.

PMID: 38224683 Generated a podocyte-specific Nup160 knockout (Nup160podKO) mouse mode using CRISPR/Cas9 and Cre/loxP technologies. They showed that Nup160podKO mice develop typical signs of NS.; to: PMID: 30910934 1 x patient with familial steroid-resistant nephrotic syndrome (SRNS) and FSGS carried novel compound-heterozygous variants in NUP160 (R1173X and E803K). Silencing of Drosophila NUP160 specifically in nephrocytes (fly renal cells) led to functional abnormalities, reduced cell size and nuclear volume, and disorganized nuclear membrane structure. These defects were completely rescued by the expression of the wild-type human NUP160 gene in nephrocytes.

PMID: 30179222 1 x family (2 sibs) with compound het variants E803K and Arg910X. 1 Sib had SRNS and FSGS, the other had proteinuria.

PMID: 33456446 1 x family (2 sibs) with SRNS and chronic kidney disease. Homozygous for NUP160 c.1179+5G>A, confirmed by RT-PCR to cause abnormal splicing [r.1102_1179del;p.(Phe368_Gln393del)]. These individuals also had additional neurological features of intellectual disability and epilepsy.

PMID: 38224683 Generated a podocyte-specific Nup160 knockout (Nup160podKO) mouse model using CRISPR/Cas9 and Cre/loxP technologies. They showed that Nup160podKO mice develop typical signs of NS.
Mendeliome v1.1513 NUP160 Melanie Marty reviewed gene: NUP160: Rating: GREEN; Mode of pathogenicity: None; Publications: 30910934, 30179222, 33456446, 38224683; Phenotypes: Steroid-resistant nephrotic syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1513 SP9 Zornitza Stark Marked gene: SP9 as ready
Mendeliome v1.1513 SP9 Zornitza Stark Gene: sp9 has been classified as Green List (High Evidence).
Mendeliome v1.1513 SP9 Suliman Khan commented on gene: SP9: PMID: 38288683: reported 5 unrelated patients with de novo heterozygous variants (missense and PTV) in SP9 gene. In silico and in vitro studies suggested a novel form of interneuronopathy with variable severity depending on the presence of loss or gain of function variants. Patients with loss-of-function variants had ID, ASD, and epilepsy, whereas missense variants in the second C2H2 binding domain result in hypomorphic and neomorphic DNA binding functions that cause severe epileptic encephalopathy. The author suggested a novel form of interneuronopathy with variable severity depending on the presence of loss or gain of function variants.
Mendeliome v1.1513 SP9 Zornitza Stark Phenotypes for gene: SP9 were changed from neurodevelopmental disorder MONDO:0700092 to neurodevelopmental disorder MONDO:0700092, SP9-related
Mendeliome v1.1512 SP9 Zornitza Stark Classified gene: SP9 as Green List (high evidence)
Mendeliome v1.1512 SP9 Zornitza Stark Gene: sp9 has been classified as Green List (High Evidence).
Mendeliome v1.1511 SP9 Suliman Khan gene: SP9 was added
gene: SP9 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SP9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SP9 were set to PMID: 38288683
Phenotypes for gene: SP9 were set to neurodevelopmental disorder MONDO:0700092
Review for gene: SP9 was set to GREEN
Added comment: Sources: Literature
Mendeliome v1.1511 MEI4 Lisa Norbart edited their review of gene: MEI4: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1511 MEI4 Lisa Norbart changed review comment from: PMID: 38252283 - 5x compound heterozygous missense variants and 1x homozygous missense variant seen in five individuals across 4 unrelated families affected with female infertility characterised by preimplantation embryonic arrest. Includes one family with two affected sisters with the same compound heterozygous variants. 2/4 families showed inheritance, parental data not available for other two families. Homozygous variant in the consanguineous family appears with a more severe phenotype.

In vitro evidence shows variants reduced the interactions between MEI4 and DNA, but no effects on protein levels. In vivo knock-out mouse model showed female mice were infertile, characterised by developmental defects during oogenesis.
Sources: Literature; to: PMID: 38252283 - 5x compound heterozygous missense variants and 1x homozygous missense variant seen in five individuals across 4 unrelated families affected with female infertility characterised by preimplantation embryonic arrest. Includes one family with two affected sisters with the same compound heterozygous variants. 2/4 families showed inheritance, parental data not available for other two families. Homozygous variant in the consanguineous family appears with a more severe phenotype.

In vitro evidence shows variants reduced the interactions between MEI4 and DNA, but no effects on protein levels. In vivo knock-out mouse model showed female mice were infertile, characterised by developmental defects during oogenesis.
Sources: Literature
Mendeliome v1.1511 CCDC88C Rylee Peters reviewed gene: CCDC88C: Rating: AMBER; Mode of pathogenicity: None; Publications: 38173219; Phenotypes: monogenic epilepsy MONDO:0015653, CCDC88C-related; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.1511 RHOXF1 Zornitza Stark Marked gene: RHOXF1 as ready
Mendeliome v1.1511 RHOXF1 Zornitza Stark Gene: rhoxf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1511 RHOXF1 Zornitza Stark Classified gene: RHOXF1 as Amber List (moderate evidence)
Mendeliome v1.1511 RHOXF1 Zornitza Stark Gene: rhoxf1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1510 MEI4 Zornitza Stark Marked gene: MEI4 as ready
Mendeliome v1.1510 MEI4 Zornitza Stark Gene: mei4 has been classified as Green List (High Evidence).
Mendeliome v1.1510 RHOXF1 Chris Ciotta gene: RHOXF1 was added
gene: RHOXF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RHOXF1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: RHOXF1 were set to PMID: 38258527
Phenotypes for gene: RHOXF1 were set to Spermatogenic failure, MONDO:0004983, RHOXF1-related
Review for gene: RHOXF1 was set to AMBER
Added comment: In a cohort of 1,201 men from China with oligozoospermia and azoospermia, hemizygous RHOXF1 variants were identified in 4 unrelated individuals.

Three of these variants were missense variants (V130M, A91V & A156V), all were absent from gnomAD (including version 4) and had deleterious in silicos.

The one other variant was a nonsense variant (R160X) which is predicted to escape NMD and truncate the protein. This is seen in gnomAD version 4 in 1 heterozygote female, and absent in other versions.

In vitro functional evidence for these variants was provided, the V130M, A156V and R160X mutants demonstrated impaired protein localisation with an increase in the protein in the cytoplasm and impaired nuclear entry, the A91V mutant protein did not share these localisation defects.

Further, The V130M mutant protein decreased DMRT1 promotor activity, DMRT1 is considered essential for testicular development and spermatogenesis. However, the R160X variant demonstrated increased activation, three times higher than WT. The two other missense variants had no effect.
Sources: Literature
Mendeliome v1.1510 PRDM6 Elena Savva Marked gene: PRDM6 as ready
Mendeliome v1.1510 PRDM6 Elena Savva Gene: prdm6 has been classified as Green List (High Evidence).
Mendeliome v1.1510 PRDM6 Elena Savva Classified gene: PRDM6 as Green List (high evidence)
Mendeliome v1.1510 PRDM6 Elena Savva Gene: prdm6 has been classified as Green List (High Evidence).
Mendeliome v1.1509 PRDM6 Elena Savva gene: PRDM6 was added
gene: PRDM6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRDM6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PRDM6 were set to 38071433; 27716515; 27181681
Phenotypes for gene: PRDM6 were set to Patent ductus arteriosus 3 MIM#617039
Review for gene: PRDM6 was set to GREEN
Added comment: Gene is established for patent ductus arteriosus. Only missense reported but supported by functional studies suggesting LOF.

PMID: 38071433 - Two families (3 affected, 6 affected) with patent ductus arteriosus with/without additional coarctation of the aorta. Family 1 had a missense, family 2 had a PTC - both regarded as VUSs

Additional papers PMID: 27716515;27181681 describe nonsyndromic patent ductus arteriosus for the first time
Sources: Literature
Mendeliome v1.1508 MEI4 Zornitza Stark Classified gene: MEI4 as Green List (high evidence)
Mendeliome v1.1508 MEI4 Zornitza Stark Gene: mei4 has been classified as Green List (High Evidence).
Mendeliome v1.1507 MEI4 Lisa Norbart gene: MEI4 was added
gene: MEI4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MEI4 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: MEI4 were set to 38252283
Phenotypes for gene: MEI4 were set to Infertility disorder, MONDO:0005047, MEI4-related
Review for gene: MEI4 was set to GREEN
Added comment: PMID: 38252283 - 5x compound heterozygous missense variants and 1x homozygous missense variant seen in five individuals across 4 unrelated families affected with female infertility characterised by preimplantation embryonic arrest. Includes one family with two affected sisters with the same compound heterozygous variants. 2/4 families showed inheritance, parental data not available for other two families. Homozygous variant in the consanguineous family appears with a more severe phenotype.

In vitro evidence shows variants reduced the interactions between MEI4 and DNA, but no effects on protein levels. In vivo knock-out mouse model showed female mice were infertile, characterised by developmental defects during oogenesis.
Sources: Literature
Mendeliome v1.1507 WDR44 Seb Lunke Marked gene: WDR44 as ready
Mendeliome v1.1507 WDR44 Seb Lunke Added comment: Comment when marking as ready: GoF mentioned but not well established.
Mendeliome v1.1507 WDR44 Seb Lunke Gene: wdr44 has been classified as Green List (High Evidence).
Mendeliome v1.1507 WDR44 Seb Lunke Classified gene: WDR44 as Green List (high evidence)
Mendeliome v1.1507 WDR44 Seb Lunke Gene: wdr44 has been classified as Green List (High Evidence).
Mendeliome v1.1506 WDR44 Andrew Fennell gene: WDR44 was added
gene: WDR44 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WDR44 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: WDR44 were set to PMID: 38191484
Phenotypes for gene: WDR44 were set to Ciliopathy, MONDO:0005308, WDR44-related
Review for gene: WDR44 was set to GREEN
Added comment: 11 male patients with 6 missense and 1 nonsense variant in WDR44 displaying a wide range of cognitive impairment and variable congenital anomalies associated with primary cilium dysfunction. All patients had learning difficulties with 8 labelled as intellectually disabled (mild-moderate). Other clinical features included anomalies of craniofacial, musculoskeletal, brain, renal and cardiac development.
WDR44 is a negative regulator of ciliogenesis. Increased binding is hypothesised to underlie the pathogenicity of WDR44 variants identified in this cohort. Functional data supported impaired ciliogenesis initiation in patient fibroblasts and a zebrafish model. A zebrafish model recapitulated the human phenotype when morphants expressed WDR44 L668S, D669N, S764F, G782C, H839R, and R733* variants. Of note, D648G or N840S did not recapitulate the phenotype in the zebrafish model.
The studies supported a GoF mechanism, but the authors could not rule out that LoF of WDR44 contributes to the ciliopathy-like phenotype observed, because protein expression data was only available for a limited number of patients.
Sources: Literature
Mendeliome v1.1506 SAMD7 Zornitza Stark Marked gene: SAMD7 as ready
Mendeliome v1.1506 SAMD7 Zornitza Stark Gene: samd7 has been classified as Green List (High Evidence).
Mendeliome v1.1506 SAMD7 Zornitza Stark Classified gene: SAMD7 as Green List (high evidence)
Mendeliome v1.1506 SAMD7 Zornitza Stark Gene: samd7 has been classified as Green List (High Evidence).
Mendeliome v1.1505 SH2B3 Ain Roesley Phenotypes for gene: SH2B3 were changed from Predisposition to haematological malignancies to Predisposition to haematological malignancies; Myeloproliferation and multi-organ autoimmunity; juvenile myelomonocytic leukemia MONDO:001190, SH2B3-related
Mendeliome v1.1504 SH2B3 Ain Roesley Publications for gene: SH2B3 were set to 26457647; 23908464; 31102422; 31173385
Mendeliome v1.1503 SH2B3 Ain Roesley Mode of inheritance for gene: SH2B3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1502 SH2B3 Ain Roesley Deleted their comment
Mendeliome v1.1502 SH2B3 Ain Roesley commented on gene: SH2B3: PMID:37206266
2x families
- hom missense variant Val402Met:
functional performed on patient's fibroblasts demonstrated increased basal pSTAT5, pSTAT3 and increased pJAK2 + pSTAT5 after stimulation with IL-3, GH, GM-CSF and EPO

- hom fs Arg148Profs*40
functional performed in zebrafish demonstrated increased number of macrophages and thrombocytes

PMID:23908464;
1 fam with 2 affecteds with dev delay + autoimmunity + (1x) ALL, hom for Asp231Gly fs*3

PMID:38152053;
JMML cohort - 2x hom missense + 2x het PTCs
Mendeliome v1.1502 SH2B3 Ain Roesley reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: None; Publications: 37206266, 23908464, 38152053; Phenotypes: Myeloproliferation and multi-organ autoimmunity, juvenile myelomonocytic leukemia MONDO:001190, SH2B3-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1502 SAMD7 Paul De Fazio gene: SAMD7 was added
gene: SAMD7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SAMD7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SAMD7 were set to 38272031
Phenotypes for gene: SAMD7 were set to Macular dystrophy, retinal, SAMD7-related MONDO:0031166
Review for gene: SAMD7 was set to GREEN
gene: SAMD7 was marked as current diagnostic
Added comment: Five biallelic variants were identified in eight individuals from six families with macular dystrophy with or without cone dysfunction. Three families were consanguineous. Mean age at first presentation was 34.8 years, range 14 to 51.

Four variants affected splicing, while one missense variant impaired the repressive activity of SAMD7. All functional work was performed using in vitro assays.
Sources: Literature
Mendeliome v1.1502 CAMK2D Elena Savva Marked gene: CAMK2D as ready
Mendeliome v1.1502 CAMK2D Elena Savva Gene: camk2d has been classified as Green List (High Evidence).
Mendeliome v1.1502 CAMK2D Elena Savva Classified gene: CAMK2D as Green List (high evidence)
Mendeliome v1.1502 CAMK2D Elena Savva Gene: camk2d has been classified as Green List (High Evidence).
Mendeliome v1.1501 CAMK2D Elena Savva gene: CAMK2D was added
gene: CAMK2D was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CAMK2D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CAMK2D were set to 38272033
Phenotypes for gene: CAMK2D were set to Neurodevelopmental disorder (MONDO#0700092), CAMK2D-related
Added comment: PMID: 38272033
- 8 patients (5/8 de novo) with mostly missense and a single splice site variant, ages range from 5 weeks to 20 years old
- Most variants functionally shown to have a GOF mechanism causing addition DCM phenotype, LOF is only neurological
- Phenotypes include dev delay (mild-severe) (7/7 patients), skeletal anomalies (7/8, scoliosis, kyphosis, involving spine/hands/feet/palate), DCM (6/8), seizures (3/8), visual anomalies (astigmatism, cortical vision impairment, myopia, strabismus 5/5), enlarged brain ventricles (3/5)
Sources: Literature
Mendeliome v1.1500 ERG Zornitza Stark Phenotypes for gene: ERG were changed from Lymphatic malformation 14, MIM# 620602 to Lymphatic malformation 14, MIM# 620602; Myelodysplasia syndrome, MONDO:0018881, ERG-related
Mendeliome v1.1499 ERG Zornitza Stark edited their review of gene: ERG: Changed rating: AMBER; Changed publications: s://ash.confex.com/ash/2023/webprogram/Paper191986.html; Changed phenotypes: Myelodysplasia syndrome, MONDO:0018881, ERG-related; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1499 RBMX Zornitza Stark Phenotypes for gene: RBMX were changed from Intellectual developmental disorder, syndromic 11, Shashi type, MIM#300238 to Intellectual developmental disorder, syndromic 11, Shashi type, MIM#300238; Gustavson syndrome, MIM# 309555
Mendeliome v1.1498 RBMX Zornitza Stark Publications for gene: RBMX were set to 25256757; 34260915
Mendeliome v1.1497 RBMX Zornitza Stark edited their review of gene: RBMX: Added comment: PMID 37277488: In-frame deletion reported in a large multiplex Swedish family; Changed publications: 25256757, 34260915, 37277488; Changed phenotypes: Intellectual developmental disorder, syndromic 11, Shashi type, MIM#300238, Gustavson syndrome, MIM# 309555
Mendeliome v1.1497 MCTS1 Zornitza Stark Phenotypes for gene: MCTS1 were changed from Inherited susceptibility to mycobacterial diseases, MONDO:0019146, MCTS1-related to Immunodeficiency 118, mycobacteriosis, MIM# 301115
Mendeliome v1.1496 MCTS1 Zornitza Stark edited their review of gene: MCTS1: Changed phenotypes: Immunodeficiency 118, mycobacteriosis, MIM# 301115
Mendeliome v1.1496 PLA2G16 Zornitza Stark Phenotypes for gene: PLA2G16 were changed from Lipodystrophy (MONDO:0006573), PLA2G16-related to Lipodystrophy, familial partial, type 9, MIM# 620683
Mendeliome v1.1495 KDM5A Elena Savva Phenotypes for gene: KDM5A were changed from autism spectrum disorder, MONDO:0005258; intellectual disability, MONDO:0001071 to autism spectrum disorder, MONDO:0005258; Neurodevelopmental disorder MONDO:0700092, KDM5A-related
Mendeliome v1.1494 JMJD1C Elena Savva Phenotypes for gene: JMJD1C were changed from Intellectual disability to Intellectual disability (MONDO#0001071), JMJD1C-related
Mendeliome v1.1493 MEIOB Zornitza Stark Phenotypes for gene: MEIOB were changed from Spermatogenic failure 22 MIM#617706; primary ovarian insufficiency to Spermatogenic failure 22 MIM#617706; Premature ovarian failure 23, MIM# 620686
Mendeliome v1.1492 MEIOB Zornitza Stark Publications for gene: MEIOB were set to 34794894; 24068956; 31000419; 28206990
Mendeliome v1.1491 MEIOB Zornitza Stark reviewed gene: MEIOB: Rating: GREEN; Mode of pathogenicity: None; Publications: 35991565, 34392356, 31000419; Phenotypes: Premature ovarian failure 23, MIM# 620686; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1491 NEPRO Zornitza Stark Publications for gene: NEPRO were set to 26633546; 29620724; 31250547
Mendeliome v1.1490 NEPRO Zornitza Stark Classified gene: NEPRO as Green List (high evidence)
Mendeliome v1.1490 NEPRO Zornitza Stark Gene: nepro has been classified as Green List (High Evidence).
Mendeliome v1.1489 NEPRO Zornitza Stark reviewed gene: NEPRO: Rating: GREEN; Mode of pathogenicity: None; Publications: 37294112; Phenotypes: Anauxetic dysplasia 3, MIM618853; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1489 RNF213 Zornitza Stark Publications for gene: RNF213 were set to
Mendeliome v1.1488 RNF213 Zornitza Stark Mode of inheritance for gene: RNF213 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1487 POLR1A Zornitza Stark Phenotypes for gene: POLR1A were changed from Acrofacial dysostosis, Cincinnati type, (MIM#616462); Leukodystrophy MONDO:0019046, POLR1A-related to Leukodystrophy, hypomyelinating, 27, MIM# 620675; Acrofacial dysostosis, Cincinnati type, (MIM#616462)
Mendeliome v1.1486 POLR1A Zornitza Stark edited their review of gene: POLR1A: Changed phenotypes: Leukodystrophy, hypomyelinating, 27, MIM# 620675, Acrofacial dysostosis, Cincinnati type, (MIM#616462)
Mendeliome v1.1486 PCYT1A Zornitza Stark Phenotypes for gene: PCYT1A were changed from Spondylometaphyseal dysplasia with cone-rod dystrophy, MIM# 608940; Congenital lipodystrophy to Spondylometaphyseal dysplasia with cone-rod dystrophy, MIM# 608940; Lipodystrophy, congenital generalized, type 5, MIM# 620680
Mendeliome v1.1485 PCYT1A Zornitza Stark edited their review of gene: PCYT1A: Changed phenotypes: Spondylometaphyseal dysplasia with cone-rod dystrophy, MIM# 608940, Lipodystrophy, congenital generalized, type 5, MIM# 620680
Mendeliome v1.1485 ATP6V0A1 Elena Savva Phenotypes for gene: ATP6V0A1 were changed from Neurodevelopmental disorder MONDO:0700092, ATP6V0A1-associated to Developmental and epileptic encephalopathy 104 MIM#619970; Neurodevelopmental disorder with epilepsy and brain atrophy MIM#619971
Mendeliome v1.1484 TREX1 Zornitza Stark Mode of inheritance for gene: TREX1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1483 FTH1 Zornitza Stark Phenotypes for gene: FTH1 were changed from Hemochromatosis, type 5, MIM# 615517; Neuroferritinopathy (MONDO:0011638) to Hemochromatosis, type 5, MIM# 615517; Neurodegeneration with brain iron accumulation 9, MIM# 620669
Mendeliome v1.1482 IRF1 Zornitza Stark Phenotypes for gene: IRF1 were changed from Inherited susceptibility to mycobacterial disease, MONDO:0019146, IRF1-related to Immunodeficiency 117, mycobacteriosis, autosomal recessive, MIM# 620668
Mendeliome v1.1481 IRF1 Zornitza Stark edited their review of gene: IRF1: Changed phenotypes: Immunodeficiency 117, mycobacteriosis, autosomal recessive, MIM# 620668
Mendeliome v1.1481 COQ4 Zornitza Stark Phenotypes for gene: COQ4 were changed from Coenzyme Q10 deficiency, primary, 7, MIM# 616276 to Coenzyme Q10 deficiency, primary, 7, MIM# 616276; Spastic ataxia 10, autosomal recessive, MIM# 620666
Mendeliome v1.1480 COQ4 Zornitza Stark Publications for gene: COQ4 were set to 25658047; 26185144; 33704555
Mendeliome v1.1479 COQ4 Zornitza Stark edited their review of gene: COQ4: Added comment: PMIDs 36047608;38014483;38013626: more than 10 families reported with more limited spastic ataxia phenotype, onset from infancy to adulthood.; Changed publications: 25658047, 26185144, 33704555, 36047608, 38014483, 38013626; Changed phenotypes: Coenzyme Q10 deficiency, primary, 7, MIM# 616276, Spastic ataxia 10, autosomal recessive, MIM# 620666
Mendeliome v1.1479 SEC61A1 Zornitza Stark Phenotypes for gene: SEC61A1 were changed from Hyperuricemic nephropathy, familial juvenile, 4, MIM# 617056; Hypogammaglobulinaemia; Neutropaenia to Hyperuricemic nephropathy, familial juvenile, 4, MIM# 617056; Immunodeficiency, common variable, 15, MIM# 620670; Neutropenia, severe congenital, 11, autosomal dominant, MIM# 620674
Mendeliome v1.1478 SEC61A1 Zornitza Stark Publications for gene: SEC61A1 were set to 27392076; 32325141; 28782633
Mendeliome v1.1477 SEC61A1 Zornitza Stark edited their review of gene: SEC61A1: Added comment: PMID 32325141: single individual with de novo missense and phenotype primarily characterised by severe neutropenia.; Changed publications: 27392076, 32325141, 28782633, 32325141
Mendeliome v1.1477 SEC61A1 Zornitza Stark edited their review of gene: SEC61A1: Changed phenotypes: Hyperuricemic nephropathy, familial juvenile, 4, MIM# 617056, Immunodeficiency, common variable, 15, MIM# 620670, Neutropenia, severe congenital, 11, autosomal dominant, MIM# 620674
Mendeliome v1.1477 SEC61A1 Zornitza Stark edited their review of gene: SEC61A1: Changed phenotypes: Hyperuricemic nephropathy, familial juvenile, 4, MIM# 617056, Immunodeficiency, common variable, 15, MIM# 620670
Mendeliome v1.1477 KPNA7 Elena Savva Phenotypes for gene: KPNA7 were changed from Oocyte/zygote/embryo maturation arrest 17, MIM# 620319; Neurodevelopmental disorder to Oocyte/zygote/embryo maturation arrest 17, MIM# 620319; Neurodevelopmental disorder (MONDO#0700092), KPNA7-related
Mendeliome v1.1476 KIF4A Elena Savva Phenotypes for gene: KIF4A were changed from Mental retardation, X-linked 100, MIM# 300923; Taurodontism, microdontia, and dens invaginatus (MIM#313490) to Intellectual developmental disorder, X-linked 100 MIM#300923; Taurodontism, microdontia, and dens invaginatus MIM#313490
Mendeliome v1.1475 KCTD13 Elena Savva Mode of inheritance for gene: KCTD13 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.1474 KCTD13 Elena Savva Phenotypes for gene: KCTD13 were changed from Intellectual disability; seizures to Neurodevelopmental disorder (MONDO#0700092), KCTD13-related
Mendeliome v1.1473 KCNN3 Elena Savva Phenotypes for gene: KCNN3 were changed from Zimmermann-Laband syndrome 3; OMIM# 618658 to Zimmermann-Laband syndrome 3; MIM#618658
Mendeliome v1.1472 KCNAB3 Elena Savva Publications for gene: KCNAB3 were set to PMID: 32990398
Mendeliome v1.1471 KCNAB3 Elena Savva reviewed gene: KCNAB3: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 37396552, 32990398, 36345448; Phenotypes: Neurodevelopmental disorder (MONDO#0700092), KCNAB3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Mendeliome v1.1471 KCNAB3 Elena Savva Phenotypes for gene: KCNAB3 were changed from febrile seizures; afebrile seizure; genetic epilepsy with febrile seizures plus to Neurodevelopmental disorder (MONDO#0700092), KCNAB3-related
Mendeliome v1.1470 JAKMIP1 Elena Savva Phenotypes for gene: JAKMIP1 were changed from Intellectual disability; Seizures to Neurodevelopmental disorder (MONDO#0700092), JAKMIP1-related
Mendeliome v1.1469 PPFIA3 Zornitza Stark Marked gene: PPFIA3 as ready
Mendeliome v1.1469 PPFIA3 Zornitza Stark Gene: ppfia3 has been classified as Green List (High Evidence).
Mendeliome v1.1469 PPFIA3 Zornitza Stark Classified gene: PPFIA3 as Green List (high evidence)
Mendeliome v1.1469 PPFIA3 Zornitza Stark Gene: ppfia3 has been classified as Green List (High Evidence).
Mendeliome v1.1468 PPFIA3 Zornitza Stark gene: PPFIA3 was added
gene: PPFIA3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPFIA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPFIA3 were set to 37034625
Phenotypes for gene: PPFIA3 were set to Neurodevelopmental disorder, MONDO:0700092, PPFIA3-related
Review for gene: PPFIA3 was set to GREEN
Added comment: 19 individuals with mono-allelic variants presenting with features including developmental delay, intellectual disability, hypotonia, micro/macrocephaly, autism, and epilepsy.

One individual with compound het variants: insufficient evidence for bi-allelic variants causing disease.
Sources: Literature
Mendeliome v1.1467 SLC13A3 Zornitza Stark Marked gene: SLC13A3 as ready
Mendeliome v1.1467 SLC13A3 Zornitza Stark Gene: slc13a3 has been classified as Green List (High Evidence).
Mendeliome v1.1467 SLC13A3 Zornitza Stark Publications for gene: SLC13A3 were set to https://www.neurology.org/doi/full/10.1212/NXG.0000000000200101 (No PMID)
Mendeliome v1.1466 SLC13A3 Zornitza Stark Classified gene: SLC13A3 as Green List (high evidence)
Mendeliome v1.1466 SLC13A3 Zornitza Stark Gene: slc13a3 has been classified as Green List (High Evidence).
Mendeliome v1.1465 MAX Zornitza Stark Phenotypes for gene: MAX were changed from {Pheochromocytoma, susceptibility to}, MIM# 171300 to {Pheochromocytoma, susceptibility to}, MIM# 171300; Syndromic disease (MONDO:0002254), MAX-related
Mendeliome v1.1464 MAX Zornitza Stark Publications for gene: MAX were set to 21685915
Mendeliome v1.1463 SPIN4 Zornitza Stark Marked gene: SPIN4 as ready
Mendeliome v1.1463 SPIN4 Zornitza Stark Gene: spin4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1463 SPIN4 Zornitza Stark Mode of inheritance for gene: SPIN4 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.1462 SPIN4 Zornitza Stark Classified gene: SPIN4 as Amber List (moderate evidence)
Mendeliome v1.1462 SPIN4 Zornitza Stark Gene: spin4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1461 GTPBP1 Zornitza Stark Marked gene: GTPBP1 as ready
Mendeliome v1.1461 GTPBP1 Zornitza Stark Gene: gtpbp1 has been classified as Green List (High Evidence).
Mendeliome v1.1461 GTPBP1 Zornitza Stark Classified gene: GTPBP1 as Green List (high evidence)
Mendeliome v1.1461 GTPBP1 Zornitza Stark Gene: gtpbp1 has been classified as Green List (High Evidence).
Mendeliome v1.1460 CACHD1 Zornitza Stark Marked gene: CACHD1 as ready
Mendeliome v1.1460 CACHD1 Zornitza Stark Gene: cachd1 has been classified as Green List (High Evidence).
Mendeliome v1.1460 CACHD1 Zornitza Stark Classified gene: CACHD1 as Green List (high evidence)
Mendeliome v1.1460 CACHD1 Zornitza Stark Gene: cachd1 has been classified as Green List (High Evidence).
Mendeliome v1.1459 CACHD1 Zornitza Stark reviewed gene: CACHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: syndromic complex neurodevelopmental disorder MONDO:0800439; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1459 SLC13A3 Daniel Flanagan gene: SLC13A3 was added
gene: SLC13A3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SLC13A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC13A3 were set to https://www.neurology.org/doi/full/10.1212/NXG.0000000000200101 (No PMID)
Phenotypes for gene: SLC13A3 were set to Leukoencephalopathy, acute reversible, with increased urinary alpha-ketoglutarate (MIM# 618384)
Review for gene: SLC13A3 was set to GREEN
Added comment: Seven patients reported with biallelic SLC13A3 variants, causing acute reversible leukoencephalopathy and α-ketoglutarate accumulation. Patients presented with acute neurological deterioration after a febrile illness. 5/7 with ataxia, 4/7 had seizures, 1/7 developmental delay.
Sources: Expert list
Mendeliome v1.1459 MAX Rylee Peters reviewed gene: MAX: Rating: GREEN; Mode of pathogenicity: None; Publications: 38141607; Phenotypes: Syndromic disease (MONDO:0002254), MAX-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1459 SOX8 Zornitza Stark Marked gene: SOX8 as ready
Mendeliome v1.1459 SOX8 Zornitza Stark Gene: sox8 has been classified as Red List (Low Evidence).
Mendeliome v1.1459 SOX8 Zornitza Stark Classified gene: SOX8 as Red List (low evidence)
Mendeliome v1.1459 SOX8 Zornitza Stark Gene: sox8 has been classified as Red List (Low Evidence).
Mendeliome v1.1458 BORCS8 Zornitza Stark Marked gene: BORCS8 as ready
Mendeliome v1.1458 BORCS8 Zornitza Stark Gene: borcs8 has been classified as Green List (High Evidence).
Mendeliome v1.1458 BORCS8 Zornitza Stark Classified gene: BORCS8 as Green List (high evidence)
Mendeliome v1.1458 BORCS8 Zornitza Stark Gene: borcs8 has been classified as Green List (High Evidence).
Mendeliome v1.1457 CACHD1 Suliman Khan gene: CACHD1 was added
gene: CACHD1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CACHD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACHD1 were set to PMID: 38158856
Phenotypes for gene: CACHD1 were set to syndromic complex neurodevelopmental disorder MONDO:0800439
Penetrance for gene: CACHD1 were set to unknown
Review for gene: CACHD1 was set to GREEN
Added comment: Sources: Literature
Mendeliome v1.1457 SPIN4 Belinda Chong gene: SPIN4 was added
gene: SPIN4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPIN4 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: SPIN4 were set to 36927955
Phenotypes for gene: SPIN4 were set to Lui-Jee-Baron syndrome MIM#301114
Review for gene: SPIN4 was set to AMBER
Added comment: PMID 36927955
* Single family, hemizygous frameshift variant (NM_001012968.3, c.312_313AGdel) identified in a male individual with generalized overgrowth of prenatal onset, variant also present in the mother and grandmother (both had adult heights 2 SDS greater than their midparental heights).
* In vitro shows loss of function and mice studies recapitulated the human phenotype with
generalized overgrowth, including increased longitudinal bone growth.
Sources: Literature
Sources: Literature
Mendeliome v1.1457 SOX8 Paul De Fazio gene: SOX8 was added
gene: SOX8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SOX8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SOX8 were set to https://www.neurology.org/doi/full/10.1212/NXG.0000000000200088
Phenotypes for gene: SOX8 were set to Neurodevelopmental disorder (MONDO:0700092), SOX8-related
Review for gene: SOX8 was set to RED
gene: SOX8 was marked as current diagnostic
Added comment: Proband presented to genetics clinic at 27 years of age with BMI -3.4SD, height -2.7SD, head circumference -1.8SD. She had mild intellectual delay and clinical features of a congenital, nonprogressive myopathy with moderate proximal and distal weakness. X-rays showed skeletal dysplasia, including cervical thoracic scoliosis and lumbar scoliosis. She was reported as having had weakness at birth with poor suck, micrognathia, hypotonia, and talipes. She was documented to have significant motor delay as a child. MRI of the brain demonstrated large posterior fossa CSF spaces.

Biallelic SOX8 variants biallelic (NM_014587.3:c.422+5G>C; c.583dup p.(His195ProfsTer11)) were identified by WGS. The +5 variant was shown to affect splicing, while the frameshift variant resulted in production of low-level truncated protein (not NMD predicted). Functional studies on patient fibroblasts showed misregulation of downstream SOX8 targets.
Sources: Literature
Mendeliome v1.1457 BORCS8 Lauren Rogers changed review comment from: 3 unrelated families with five affected children with homozygous or compound heterozygous loss of function missense and PTC variants.

HEK293T cells show the missense variants are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution. The BORCS8 PTC frameshift variant is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution. Zebrafish KO of the orthologous brocs8 causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease.
Sources: Literature; to: 3 unrelated families with five affected children with homozygous or compound heterozygous loss of function missense and PTC variants. 5/5 hypotonia, failure to thrive, global developmental delay, profound intellectual disability, muscle weakness and atrophy, dysmorphic features. 3/5 with microcephaly, 3/5 with seizures, 4/5 with spasticity, 3/5 with scoliosis, 4/4 with optic atrophy.

HEK293T cells show the missense variants are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution. The BORCS8 PTC frameshift variant is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution. Zebrafish KO of the orthologous brocs8 causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease.
Sources: Literature
Mendeliome v1.1457 BORCS8 Lauren Rogers gene: BORCS8 was added
gene: BORCS8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: BORCS8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS8 were set to 38128568
Phenotypes for gene: BORCS8 were set to Neurodevelopmental disorder (MONDO#0700092), BORCS8-related
Review for gene: BORCS8 was set to GREEN
Added comment: 3 unrelated families with five affected children with homozygous or compound heterozygous loss of function missense and PTC variants.

HEK293T cells show the missense variants are expressed at normal levels but exhibit reduced assembly with other BORC subunits and reduced ability to drive lysosome distribution. The BORCS8 PTC frameshift variant is expressed at lower levels and is completely incapable of assembling with other BORC subunits and promoting lysosome distribution. Zebrafish KO of the orthologous brocs8 causes decreased brain and eye size, neuromuscular anomalies and impaired locomotion, recapitulating some of the key traits of the human disease.
Sources: Literature
Mendeliome v1.1457 GTPBP1 Lucy Spencer gene: GTPBP1 was added
gene: GTPBP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTPBP1 were set to 38118446
Phenotypes for gene: GTPBP1 were set to Neurodevelopmental disorder (MONDO#0700092), GTPBP1-related
Review for gene: GTPBP1 was set to GREEN
Added comment: PMID: 38118446- Cohort of individuals with variants in GTPBP2 (which has been previously described) and GTPBP1 (new) who have an identical neurodevelopmental syndrome. 4 homozygous individuals from 3 consanguineous families. 2 families have different NMD-predicted nonsense variants and the third has a missense, all are absent from gnomad v4.

The shared cardinal features of GTPBP1 and 2 related disease are microcephaly, profound neurodevelopmental impairment, and distinctive craniofacial features. Epilepsy was present in 10 of 20 individuals but its not clear if those individuals had GTPBP1 or 2 variants.
Sources: Literature
Mendeliome v1.1457 RAPGEF2 Zornitza Stark Tag STR tag was added to gene: RAPGEF2.
Mendeliome v1.1457 PTBP1 Zornitza Stark Marked gene: PTBP1 as ready
Mendeliome v1.1457 PTBP1 Zornitza Stark Gene: ptbp1 has been classified as Red List (Low Evidence).
Mendeliome v1.1457 PTBP1 Zornitza Stark Classified gene: PTBP1 as Red List (low evidence)
Mendeliome v1.1457 PTBP1 Zornitza Stark Gene: ptbp1 has been classified as Red List (Low Evidence).
Mendeliome v1.1456 PUS3 Zornitza Stark Phenotypes for gene: PUS3 were changed from Mental retardation, autosomal recessive 55, MIM# 617051 to Neurodevelopmental disorder with microcephaly and gray sclerae, MIM# 617051
Mendeliome v1.1455 PUS3 Zornitza Stark edited their review of gene: PUS3: Changed phenotypes: Neurodevelopmental disorder with microcephaly and gray sclerae, MIM# 617051
Mendeliome v1.1455 RAPGEF2 Belinda Chong gene: RAPGEF2 was added
gene: RAPGEF2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAPGEF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAPGEF2 were set to 37021642; 30351492; 29507423
Phenotypes for gene: RAPGEF2 were set to ?Epilepsy, familial adult myoclonic, 7 MIM# 618075
Review for gene: RAPGEF2 was set to RED
Added comment: Heterozygous 5-bp repeat expansion (TTTCA(n)) in intron 14 of RAPGEF2 gene. Two individuals previously reported (PMID: 30351492 and 29507423) with seizures
Sources: Literature
Mendeliome v1.1455 PTBP1 Belinda Chong gene: PTBP1 was added
gene: PTBP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTBP1 was set to Unknown
Review for gene: PTBP1 was set to RED
Added comment: No evidence for Mendelian disease association.
Sources: Literature
Mendeliome v1.1455 ALG8 Zornitza Stark Publications for gene: ALG8 were set to 26066342; 28375157; 15235028
Mendeliome v1.1454 PRICKLE2 Zornitza Stark changed review comment from: LIMITED by ClinGen.; to: LIMITED by ClinGen; however, experimental evidence appears not to have been considered.
Mendeliome v1.1454 PRICKLE2 Zornitza Stark Phenotypes for gene: PRICKLE2 were changed from Neurodevelopmental disorder, MONDO:0700092; global developmental delay, behavioural difficulties ± epilepsy, autistic features, and attention deficit hyperactive disorder. to Neurodevelopmental disorder MONDO:0700092, PRICKLE2-related
Mendeliome v1.1453 PRICKLE2 Zornitza Stark Publications for gene: PRICKLE2 were set to 34092786
Mendeliome v1.1452 PRICKLE2 Zornitza Stark Classified gene: PRICKLE2 as Amber List (moderate evidence)
Mendeliome v1.1452 PRICKLE2 Zornitza Stark Gene: prickle2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1451 PRICKLE2 Zornitza Stark reviewed gene: PRICKLE2: Rating: AMBER; Mode of pathogenicity: None; Publications: 34092786, 21276947, 26942291, 26942292; Phenotypes: Neurodevelopmental disorder MONDO:0700092, PRICKLE2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1451 PRICKLE1 Zornitza Stark Classified gene: PRICKLE1 as Red List (low evidence)
Mendeliome v1.1451 PRICKLE1 Zornitza Stark Gene: prickle1 has been classified as Red List (Low Evidence).
Mendeliome v1.1450 PRICKLE1 Zornitza Stark edited their review of gene: PRICKLE1: Added comment: LIMITED by ClinGen for AR PME and DISPUTED for AD epilepsy.; Changed rating: RED
Mendeliome v1.1450 PRICKLE1 Zornitza Stark Classified gene: PRICKLE1 as Amber List (moderate evidence)
Mendeliome v1.1450 PRICKLE1 Zornitza Stark Gene: prickle1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1449 PRICKLE1 Zornitza Stark edited their review of gene: PRICKLE1: Added comment: Note all ClinVar entries for this gene are VOUS/LB/B. The variants reported in bi-allelic cases are almost all missense without further supportive data.; Changed rating: AMBER
Mendeliome v1.1449 ERI1 Zornitza Stark Phenotypes for gene: ERI1 were changed from Spondyloepimetaphyseal dysplasia (MONDO#0100510), ERI1-related, Intellectual disability (MONDO#0001071), ERI1-related to Hoxha-Aliu syndrome, MIM# 620662; Spondyloepimetaphyseal dysplasia, Guo-Salian type, MIM# 620663
Mendeliome v1.1448 ERI1 Zornitza Stark reviewed gene: ERI1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hoxha-Aliu syndrome, MIM# 620662, Spondyloepimetaphyseal dysplasia, Guo-Salian type, MIM# 620663; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1448 ALG8 Rylee Peters reviewed gene: ALG8: Rating: GREEN; Mode of pathogenicity: None; Publications: 35716054; Phenotypes: Congenital disorder of glycosylation, type Ih, MIM# 608104; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1448 RAP1B Zornitza Stark Phenotypes for gene: RAP1B were changed from Syndromic disease, MONDO:0002254, RAP1B-related; intellectual disability; microcephaly; thrombocytopaenia to Thrombocytopenia 1 with multiple congenital anomalies and dysmorphic facies, MIM# 620654
Mendeliome v1.1447 RAP1B Zornitza Stark edited their review of gene: RAP1B: Changed phenotypes: Thrombocytopenia 1 with multiple congenital anomalies and dysmorphic facies, MIM# 620654
Mendeliome v1.1447 GPT2 Zornitza Stark Phenotypes for gene: GPT2 were changed from Mental retardation, autosomal recessive 49, MIM#616281 to Neurodevelopmental disorder with microcephaly and spastic paraplegia, MIM# 616281
Mendeliome v1.1446 GPT2 Zornitza Stark edited their review of gene: GPT2: Added comment: 10 families reported.; Changed publications: 27601654, 25758935, 31471722
Mendeliome v1.1446 GPT2 Zornitza Stark edited their review of gene: GPT2: Changed phenotypes: Neurodevelopmental disorder with microcephaly and spastic paraplegia, MIM# 616281
Mendeliome v1.1446 POLD1 Zornitza Stark Phenotypes for gene: POLD1 were changed from Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, MIM# 615381; MONDO:0014157 to Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, MIM# 615381; MONDO:0014157; Combined immunodeficiency, MONDO:0015131, POLD1-related
Mendeliome v1.1445 POLD1 Zornitza Stark Publications for gene: POLD1 were set to 23770608; 33618333; 33369179; 32826474; 30023403; 29199204; 28791128
Mendeliome v1.1444 POLD1 Zornitza Stark Mode of inheritance for gene: POLD1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1443 POLD1 Zornitza Stark edited their review of gene: POLD1: Added comment: Association with combined immunodeficiency: Three individuals from two generations of a consanguineous family reported, some functional data. Another unrelated individual reported in PMID 31449058, more functional data. Third family identified in Melbourne, two affected sibs, compound het variants and combined immunodeficiency.; Changed phenotypes: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, MIM# 615381, MONDO:0014157, Combined immunodeficiency, MONDO:0015131, POLD1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1443 LCK Zornitza Stark Classified gene: LCK as Green List (high evidence)
Mendeliome v1.1443 LCK Zornitza Stark Gene: lck has been classified as Green List (High Evidence).
Mendeliome v1.1442 LCK Zornitza Stark edited their review of gene: LCK: Added comment: Additional cases:
PMID 38100037: Description of a second unrelated patient with novel biallelic missense LCK c.1393T>C, p.C465R variant in a patient from a consanguineous Syrian family with profound T-cell immune deficiency characterized by complete LCK protein expression deficiency and ensuing proximal TCR signaling-and CD4 and CD8-co-receptor-mediated functional and phenotypical defects.

PMID: 27087313 reported 3 siblings of a consanguineous family presenting with recurrent pneumonia and severe viral skin disease leading to malignant transformation. The patients had an intronic LCK c.188-2A>G splice site variant resulting in skipping of exon 3 and mRNA decay. Clinical data alongside with CD4+ T-cell lymphocytopenia suggested a hypomorphic LCK deficiency.; Changed rating: GREEN; Changed publications: 22985903, 1579166, 11021796, 27087313, 38100037
Mendeliome v1.1442 RAP1GDS1 Zornitza Stark Phenotypes for gene: RAP1GDS1 were changed from Intellectual disability; dysmorphic features to Alfadhel syndrome, MIM# 620655
Mendeliome v1.1441 RAP1GDS1 Zornitza Stark edited their review of gene: RAP1GDS1: Changed phenotypes: Alfadhel syndrome, MIM# 620655
Mendeliome v1.1441 CASP2 Zornitza Stark Phenotypes for gene: CASP2 were changed from neurodevelopmental disorder MONDO:0700092, CASP2-related to Intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly, MIM# 620653
Mendeliome v1.1440 CASP2 Zornitza Stark reviewed gene: CASP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly, MIM# 620653; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1440 RBFOX1 Zornitza Stark Phenotypes for gene: RBFOX1 were changed from Intellectual disability; autism to Neurodevelopmental disorder (MONDO:0700092), RBFOX1-related
Mendeliome v1.1439 RBFOX1 Zornitza Stark Publications for gene: RBFOX1 were set to 24664471
Mendeliome v1.1438 RBFOX1 Zornitza Stark Classified gene: RBFOX1 as Green List (high evidence)
Mendeliome v1.1438 RBFOX1 Zornitza Stark Gene: rbfox1 has been classified as Green List (High Evidence).
Mendeliome v1.1437 BRD4 Zornitza Stark Phenotypes for gene: BRD4 were changed from Cornelia de Lange syndrome, MONDO:0016033 to Cornelia de Lange syndrome 6, MIM# 620568
Mendeliome v1.1436 BRD4 Zornitza Stark edited their review of gene: BRD4: Changed phenotypes: Cornelia de Lange syndrome 6, MIM# 620568
Mendeliome v1.1436 MAP1LC3B2 Zornitza Stark Marked gene: MAP1LC3B2 as ready
Mendeliome v1.1436 MAP1LC3B2 Zornitza Stark Gene: map1lc3b2 has been classified as Red List (Low Evidence).
Mendeliome v1.1436 MAP1LC3B2 Zornitza Stark gene: MAP1LC3B2 was added
gene: MAP1LC3B2 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: MAP1LC3B2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAP1LC3B2 were set to 35748970; 33310865
Phenotypes for gene: MAP1LC3B2 were set to Hereditary susceptibility to infection, MONDO:0015979, MAP1LC3B2 -related; Mollaret’s meningitis (recurrent lymphocytic meningitis) due to HSV2
Review for gene: MAP1LC3B2 was set to RED
Added comment: PMID: 35748970 Affects CNS (resident cells and fibroblasts) Impaired autophagy induction after HSV2 infection - increased viral replication and apoptosis of patient fibroblasts.

PMID: 33310865 one affected individual with heterozygous variant in MAP1LC3B2 (p.L109M)
Sources: Expert Review
Mendeliome v1.1435 CAPRIN1 Zornitza Stark Phenotypes for gene: CAPRIN1 were changed from Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, MIM# 620636 to Neurodevelopmental disorder, CAPRIN1-related MONDO:0700092; Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, MIM# 620636
Mendeliome v1.1434 CAPRIN1 Zornitza Stark Publications for gene: CAPRIN1 were set to 35979925
Mendeliome v1.1433 CAPRIN1 Zornitza Stark edited their review of gene: CAPRIN1: Added comment: Two individuals reported with the same de novo c.1535C > T (p.Pro512Leu) variant and a progressive course.; Changed rating: AMBER; Changed publications: 36136249
Mendeliome v1.1433 CAPRIN1 Zornitza Stark Phenotypes for gene: CAPRIN1 were changed from Neurodevelopmental disorder, CAPRIN1-related MONDO:0700092 to Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, MIM# 620636
Mendeliome v1.1432 CAPRIN1 Zornitza Stark reviewed gene: CAPRIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, MIM# 620636; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1432 MANF Zornitza Stark Marked gene: MANF as ready
Mendeliome v1.1432 MANF Zornitza Stark Gene: manf has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1432 MANF Zornitza Stark Classified gene: MANF as Amber List (moderate evidence)
Mendeliome v1.1432 MANF Zornitza Stark Gene: manf has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1431 MANF Zornitza Stark gene: MANF was added
gene: MANF was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: MANF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MANF were set to 26077850; 33500254; 34815294
Phenotypes for gene: MANF were set to Diabetes, deafness, developmental delay, and short stature syndrome, MIM# 620651
Review for gene: MANF was set to AMBER
Added comment: Two individuals reported with homozygous variants. Mouse model recapitulates deafness phenotype.
Sources: Expert Review
Mendeliome v1.1430 RRM1 Zornitza Stark Phenotypes for gene: RRM1 were changed from Multiple mitochondrial DNA deletion syndrome (MONDO:0016797) to Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 6, MIM# 620647
Mendeliome v1.1429 DRG1 Zornitza Stark Phenotypes for gene: DRG1 were changed from Neurodevelopmental disorder (MONDO:0700092), DRG1-related to Tan-Almurshedi syndrome, MIM# 620641
Mendeliome v1.1428 GABRA4 Zornitza Stark Marked gene: GABRA4 as ready
Mendeliome v1.1428 GABRA4 Zornitza Stark Gene: gabra4 has been classified as Red List (Low Evidence).
Mendeliome v1.1428 GABRA4 Zornitza Stark gene: GABRA4 was added
gene: GABRA4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GABRA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GABRA4 were set to 35152403
Phenotypes for gene: GABRA4 were set to Developmental and epileptic encephalopathy MONDO:0100062, GABRA4-related
Review for gene: GABRA4 was set to RED
Added comment: Single individual with de novo missense variant reported, supportive functional data.
Sources: Literature
Mendeliome v1.1427 PLA2G16 Zornitza Stark Marked gene: PLA2G16 as ready
Mendeliome v1.1427 PLA2G16 Zornitza Stark Added comment: Comment when marking as ready: HGNC name is PLAAT3
Mendeliome v1.1427 PLA2G16 Zornitza Stark Gene: pla2g16 has been classified as Green List (High Evidence).
Mendeliome v1.1427 PLA2G16 Zornitza Stark Tag new gene name tag was added to gene: PLA2G16.
Mendeliome v1.1427 FOXL1 Zornitza Stark Marked gene: FOXL1 as ready
Mendeliome v1.1427 FOXL1 Zornitza Stark Gene: foxl1 has been classified as Red List (Low Evidence).
Mendeliome v1.1427 FOXL1 Zornitza Stark Classified gene: FOXL1 as Red List (low evidence)
Mendeliome v1.1427 FOXL1 Zornitza Stark Gene: foxl1 has been classified as Red List (Low Evidence).
Mendeliome v1.1426 RBFOX1 Dean Phelan reviewed gene: RBFOX1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37962958; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), RBFOX1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1426 MGP Zornitza Stark Phenotypes for gene: MGP were changed from Keutel syndrome, MIM #245150 to Keutel syndrome, MIM #245150; Skeletal dysplasia MONDO:0018230, MGP-related
Mendeliome v1.1425 MGP Zornitza Stark Publications for gene: MGP were set to 9916809; 15810001; 33996798
Mendeliome v1.1424 MGP Zornitza Stark Mode of inheritance for gene: MGP was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1423 KIF5B Zornitza Stark Phenotypes for gene: KIF5B were changed from Skeletal dysplasia, MONDO:0018230, KIF5B-related; Kyphomelic dysplasia to osteogenesis imperfecta, MONDO:0019019; Skeletal dysplasia, MONDO:0018230, KIF5B-related; Kyphomelic dysplasia
Mendeliome v1.1422 KIF5B Zornitza Stark Publications for gene: KIF5B were set to PMID: 35342932; 36018820
Mendeliome v1.1421 KIF5B Zornitza Stark edited their review of gene: KIF5B: Added comment: Four additional patients with three distinct de-novo missense variants and features consistent with osteogenesis imperfecta. All variants are in the Kinesin motor domain (~50% of the protein). Functional data in C. Elegans and cell lines shows impaired protein function. Not clear what distinguishes OI causing variants from other phenotypes for this gene at this stage. Dominant negative effect proposed but not conclusively proven.; Changed publications: 37934770; Changed phenotypes: Skeletal dysplasia, MONDO:0018230, osteogenesis imperfecta, MONDO:0019019
Mendeliome v1.1421 PRPF19 Zornitza Stark Marked gene: PRPF19 as ready
Mendeliome v1.1421 PRPF19 Zornitza Stark Gene: prpf19 has been classified as Green List (High Evidence).
Mendeliome v1.1421 PRPF19 Zornitza Stark Classified gene: PRPF19 as Green List (high evidence)
Mendeliome v1.1421 PRPF19 Zornitza Stark Gene: prpf19 has been classified as Green List (High Evidence).
Mendeliome v1.1420 PLA2G16 Zornitza Stark Marked gene: PLA2G16 as ready
Mendeliome v1.1420 PLA2G16 Zornitza Stark Gene: pla2g16 has been classified as Green List (High Evidence).
Mendeliome v1.1420 PLA2G16 Zornitza Stark Phenotypes for gene: PLA2G16 were changed from Lipodystrophy (MONDO:0006573) to Lipodystrophy (MONDO:0006573), PLA2G16-related
Mendeliome v1.1419 PLA2G16 Zornitza Stark Mode of inheritance for gene: PLA2G16 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1418 PLA2G16 Zornitza Stark Classified gene: PLA2G16 as Green List (high evidence)
Mendeliome v1.1418 PLA2G16 Zornitza Stark Gene: pla2g16 has been classified as Green List (High Evidence).
Mendeliome v1.1417 OTOA Zornitza Stark Tag SV/CNV tag was added to gene: OTOA.
Mendeliome v1.1417 STRC Zornitza Stark Tag SV/CNV tag was added to gene: STRC.
Mendeliome v1.1417 SLC19A1 Zornitza Stark Phenotypes for gene: SLC19A1 were changed from Megaloblastic anemia, folate-responsive, MIM# 601775 to Megaloblastic anemia, folate-responsive, MIM# 601775; Combined immunodeficiency, SLC19A1-related MONDO:0015131
Mendeliome v1.1416 RAB1A Zornitza Stark Marked gene: RAB1A as ready
Mendeliome v1.1416 RAB1A Zornitza Stark Gene: rab1a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1416 RAB1A Zornitza Stark Classified gene: RAB1A as Amber List (moderate evidence)
Mendeliome v1.1416 RAB1A Zornitza Stark Gene: rab1a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1415 RAB1A Zornitza Stark gene: RAB1A was added
gene: RAB1A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB1A were set to 37924809
Phenotypes for gene: RAB1A were set to neurodevelopmental disorder MONDO:0700092, RAB1A-related
Review for gene: RAB1A was set to AMBER
Added comment: Four families and 5 individuals, 2/5 have speech delay and 4/5 have motor delay. Anxiety in 3/5 and autism in 2/5. Microcephaly in only one individual, spastic paraplegia observed in 2 individuals from one family. In 2 families variants were inherited from an affected parent.
Sources: Literature
Mendeliome v1.1414 CRELD1 Zornitza Stark Publications for gene: CRELD1 were set to 22740159
Mendeliome v1.1413 FUK Zornitza Stark Publications for gene: FUK were set to 30503518
Mendeliome v1.1412 FUK Zornitza Stark Classified gene: FUK as Green List (high evidence)
Mendeliome v1.1412 FUK Zornitza Stark Gene: fuk has been classified as Green List (High Evidence).
Mendeliome v1.1411 FUK Zornitza Stark edited their review of gene: FUK: Added comment: PMID: 35718084: Reporting on 3 unrelated patients from literature and 1 new patient. All reported to have mild-severe intellectual disability, developmental delay and brain abnormalities, and 3/4 present with seizures. Phenotypes are childhood onset. Homozygous and compound heterozygous variants have been reported.

PMID: 36426412: Reporting on new 1 patient (homozygous missense). Not affected by intellectual disability, developmental delay, or brain abnormalities. Presents with seizures. Loss of function suggested due to depletion of the FUK gene expression.; Changed rating: GREEN; Changed publications: 30503518, 35718084, 36426412
Mendeliome v1.1411 SV2A Zornitza Stark Marked gene: SV2A as ready
Mendeliome v1.1411 SV2A Zornitza Stark Gene: sv2a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1411 SV2A Zornitza Stark Phenotypes for gene: SV2A were changed from Epilepsy, MONDO:0005027 to Neurodevelopmental disorder, MONDO:0700092, SV2A-related
Mendeliome v1.1410 SV2A Zornitza Stark Classified gene: SV2A as Amber List (moderate evidence)
Mendeliome v1.1410 SV2A Zornitza Stark Gene: sv2a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1409 SV2A Zornitza Stark changed review comment from: Insufficient evidence for either the mono- or bi-allelic association: two convincing families with each.; to: Insufficient evidence for either the mono- or bi-allelic association: two convincing families with each.
Mendeliome v1.1409 SV2A Zornitza Stark reviewed gene: SV2A: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, SV2A-related; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.1409 CEP192 Zornitza Stark Marked gene: CEP192 as ready
Mendeliome v1.1409 CEP192 Zornitza Stark Gene: cep192 has been classified as Red List (Low Evidence).
Mendeliome v1.1409 CEP192 Zornitza Stark Classified gene: CEP192 as Red List (low evidence)
Mendeliome v1.1409 CEP192 Zornitza Stark Gene: cep192 has been classified as Red List (Low Evidence).
Mendeliome v1.1408 CEP192 Chern Lim gene: CEP192 was added
gene: CEP192 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CEP192 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CEP192 were set to 37981762
Phenotypes for gene: CEP192 were set to microcephaly, short stature, limb-extremity dysplasia, and reduced testicular size
Review for gene: CEP192 was set to RED
gene: CEP192 was marked as current diagnostic
Added comment: PMID: 37981762:
- In one family, chet missense p.His638Tyr and p.Asn1917Ser segregated with microcephaly, short stature, limb-extremity dysplasia, and reduced testicular size in two affected siblings. Both sibs also fulfilled dx for mosaic variegated aneuploidy (MVA) syndrome and have tetraploidy.
- A lower but substantial proportion of MVA/tetraploidy cells was observed in II-1, II-2, and II-4 (who are het for one of the variants).

- In the same family, each variants in heterozygous state segregated with infertility and/or reduced testicular size in the proband’s father and maternal uncle.
- Variant screening of CEP192 coding regions performed for 1264 unrelated males with idiopathic infertility.
- Asn1917Ser was also detected in three additional unrelated infertile males with reduced testicular volumes.
- Two other missense and two synonymous variants were repeatedly detected in infertile males.

- qPCR showed CEP192 expression was decreased in individuals with c.1912C>T His638Tyr, mini-gene assay showed that c.1912C>T His638Tyr led to the skipping of exon 14, predicted to result in NMD.
- Epithelial cells cultured in vitro from patients with biallelic variants showed the number of cells arrested during the prophase increased because of the failure of spindle formation.

- Embyronic mouse lethality in Cep192-/- (hom for His638Tyr), Cep192M/M (hom for Asn1917Ser) and Cep192-/M (chet).
- Embryos of Cep192M/M mice had significant increase of MVA and tetraploidy cells.
- Number of apoptotic cells increased in Cep192M/M embryos compared with that of Cep192+/+, similar result in Cep192-/- embryos.
- Male mice with Cep192 heterozygous variants replicated infertility

Conclusions:
- Association of this gene with autosomal recessive disease has not been established.
- Association of monoallelic variants in this gene with infertility is not well established:
- Two variants with some supportive evidence from mouse model.
Sources: Literature
Mendeliome v1.1408 SV2A Karina Sandoval changed review comment from: Monoallelic variants cause epilepsy. Biallelic variant in this 5yo (Hom p.Arg383Gln) reported to cause severe phenotype of drug-resistant epileptic encephalopathy with microcephaly, DD, movement disorder and growth retardation. Consanguineous.
This paper references 5 other families with both AR & AD
Family #1 – p.Arg383Gln, AR, 2 affected in family, parents healthy carriers
Family #2 – p.Arg570Cys, AD, 2 affected, inherited from affected mother (in gnomAD v2 1 het, absent from gnomAD v3)
Family #3 – p.Gly660Arg, AD, de novo
Family #4 – p.Gly660Arg, AD, segregated in 11 family members
Family #5 (this study) – p.Arg289Ter, AR, parents and 2 sibs asymptomatic carriers
Sources: Literature; to: Monoallelic variants cause epilepsy. Biallelic variant in this 5yo with p.Arg289Ter and another 5yo from another paper with homozygous p.Arg383Gln, reported to cause severe phenotype of drug-resistant epileptic encephalopathy with microcephaly, DD, movement disorder and growth retardation.
This paper references 5 other families with both AR & AD
Family #1 – p.Arg383Gln, AR, 2 affected in family, parents healthy carriers
Family #2 – p.Arg570Cys, AD, 2 affected, inherited from affected mother (in gnomAD v2 1 het, absent from gnomAD v3)
Family #3 – p.Gly660Arg, AD, de novo
Family #4 – p.Gly660Arg, AD, segregated in 11 family members
Family #5 (this study) – p.Arg289Ter, AR, parents and 2 sibs asymptomatic carriers
Sources: Literature
Mendeliome v1.1408 SV2A Karina Sandoval changed review comment from: Monoallelic variants cause epilepsy. Biallelic variant in this 5yo (Hom p.Arg383Gln) reported to cause severe phenotype of drug-resistant epileptic encephalopathy with microcephaly, DD, movement disorder and growth retardation. Consanguineous.
This paper references 5 other families with both AR & AD
Family #1 – p.Arg383Gln, AR, 2 affected in family, parents healthy carriers
Family #2 – p.Arg570Cys, AD, 2 affected, inherited from affected mother
Family #3 – p.Gly660Arg, AD, de novo
Family #4 – p.Gly660Arg, AD, segregated in 11 family members
Family #5 (this study) – p.Arg289Ter, AR, parents and 2 sibs asymptomatic carriers
Sources: Literature; to: Monoallelic variants cause epilepsy. Biallelic variant in this 5yo (Hom p.Arg383Gln) reported to cause severe phenotype of drug-resistant epileptic encephalopathy with microcephaly, DD, movement disorder and growth retardation. Consanguineous.
This paper references 5 other families with both AR & AD
Family #1 – p.Arg383Gln, AR, 2 affected in family, parents healthy carriers
Family #2 – p.Arg570Cys, AD, 2 affected, inherited from affected mother (in gnomAD v2 1 het, absent from gnomAD v3)
Family #3 – p.Gly660Arg, AD, de novo
Family #4 – p.Gly660Arg, AD, segregated in 11 family members
Family #5 (this study) – p.Arg289Ter, AR, parents and 2 sibs asymptomatic carriers
Sources: Literature
Mendeliome v1.1408 CRELD1 Naomi Baker reviewed gene: CRELD1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37947183; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), CRELD1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1408 SLC19A1 Elena Savva Classified gene: SLC19A1 as Amber List (moderate evidence)
Mendeliome v1.1408 SLC19A1 Elena Savva Gene: slc19a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1407 DDX17 Elena Savva Classified gene: DDX17 as Green List (high evidence)
Mendeliome v1.1407 DDX17 Elena Savva Gene: ddx17 has been classified as Green List (High Evidence).
Mendeliome v1.1406 DDX17 Elena Savva Classified gene: DDX17 as Green List (high evidence)
Mendeliome v1.1406 DDX17 Elena Savva Gene: ddx17 has been classified as Green List (High Evidence).
Mendeliome v1.1405 DDX17 Elena Savva Marked gene: DDX17 as ready
Mendeliome v1.1405 DDX17 Elena Savva Gene: ddx17 has been removed from the panel.
Mendeliome v1.1405 DDX17 Melanie Marty gene: DDX17 was added
gene: DDX17 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DDX17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DDX17 were set to https://www.medrxiv.org/search/DDX17
Phenotypes for gene: DDX17 were set to Neurodevelopmental disorder (MONDO#0700092), DDX17-related
Review for gene: DDX17 was set to GREEN
Added comment: https://www.medrxiv.org/search/DDX17 (pre-print)
11 patients with het de novo variants in DDX17 (5 NMD, 6 missense). Patient's phenotype included mild-moderate intellectual disability, delayed speech and language development and global developmental delay. 64% had dysmorphic facial features. Some patients also have gross and fine motor delay, generalized hypotonia, stereotypy, and evidence of autism spectrum disorder.

Knockdown of Ddx17 in newborn mice showed impaired axon outgrowth and reduced axon outgrowth and branching was observed in primary cortical neurons in vitro. This result was replicated in Crispant Xenopus tadpoles, which had clear functional neural defects and showed an impaired neurobehavioral phenotype.
Sources: Literature
Mendeliome v1.1405 SV2A Karina Sandoval gene: SV2A was added
gene: SV2A was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SV2A was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: SV2A were set to PMID: 37985816
Phenotypes for gene: SV2A were set to Epilepsy, MONDO:0005027
Review for gene: SV2A was set to GREEN
Added comment: Monoallelic variants cause epilepsy. Biallelic variant in this 5yo (Hom p.Arg383Gln) reported to cause severe phenotype of drug-resistant epileptic encephalopathy with microcephaly, DD, movement disorder and growth retardation. Consanguineous.
This paper references 5 other families with both AR & AD
Family #1 – p.Arg383Gln, AR, 2 affected in family, parents healthy carriers
Family #2 – p.Arg570Cys, AD, 2 affected, inherited from affected mother
Family #3 – p.Gly660Arg, AD, de novo
Family #4 – p.Gly660Arg, AD, segregated in 11 family members
Family #5 (this study) – p.Arg289Ter, AR, parents and 2 sibs asymptomatic carriers
Sources: Literature
Mendeliome v1.1405 MARK4 Elena Savva Classified gene: MARK4 as Red List (low evidence)
Mendeliome v1.1405 MARK4 Elena Savva Gene: mark4 has been classified as Red List (Low Evidence).
Mendeliome v1.1404 MARK4 Elena Savva Classified gene: MARK4 as Red List (low evidence)
Mendeliome v1.1404 MARK4 Elena Savva Gene: mark4 has been classified as Red List (Low Evidence).
Mendeliome v1.1403 RNF213 Seb Lunke changed review comment from: 14 individuals from 13 unrelated families with (de novo) missensevariants in RNF213 clustering within or around the RING domain. Individuals presented either with early-onset stroke (n=11) or with Leigh syndrome (n=3). No genotype-phenotype correlation could be established. Common features included Global Developmental Delay and Seizures, increased serum lactate, ischemic stroke, Moyamoya phenomenon and carotid/cerebral artery stenosis. Onset of symptoms generally in the first 6 months of life.; to: 14 individuals from 13 unrelated families with (de novo) missensevariants in RNF213 clustering within or around the RING domain. Individuals presented either with early-onset stroke (n=11) or with Leigh syndrome like symptoms (n=3). No genotype-phenotype correlation could be established. Common features included Global Developmental Delay and Seizures, increased serum lactate, ischemic stroke, and carotid/cerebral artery stenosis. Onset of symptoms generally in the first 6 months of life. Moyamoya phenomenon was present in 10/13 individuals.
Mendeliome v1.1403 MARK4 Elena Savva Marked gene: MARK4 as ready
Mendeliome v1.1403 MARK4 Elena Savva Gene: mark4 has been removed from the panel.
Mendeliome v1.1403 SLC19A1 Paul De Fazio edited their review of gene: SLC19A1: Changed rating: AMBER
Mendeliome v1.1403 ACBD6 Lucy Spencer edited their review of gene: ACBD6: Changed publications: 37951597, 36457943, 21937992, 35446914
Mendeliome v1.1403 KCNJ3 Zornitza Stark Marked gene: KCNJ3 as ready
Mendeliome v1.1403 KCNJ3 Zornitza Stark Gene: kcnj3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1403 KCNJ3 Zornitza Stark Classified gene: KCNJ3 as Amber List (moderate evidence)
Mendeliome v1.1403 KCNJ3 Zornitza Stark Gene: kcnj3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1402 RNF213 Seb Lunke edited their review of gene: RNF213: Changed phenotypes: Moyamoya disease, MONDO:0016820, pediatric arterial ischemic stroke, MONDO:0018585
Mendeliome v1.1402 SLC19A1 Paul De Fazio reviewed gene: SLC19A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36517554, 36745868; Phenotypes: Combined immunodeficiency, SLC19A1-related MONDO:0015131; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1402 PLA2G16 Lauren Rogers edited their review of gene: PLA2G16: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1402 KCNJ3 Daniel Flanagan gene: KCNJ3 was added
gene: KCNJ3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: KCNJ3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNJ3 were set to PMID: 37963718
Phenotypes for gene: KCNJ3 were set to Epilepsy (MONDO#0005027), KCNJ3-related
Review for gene: KCNJ3 was set to AMBER
Added comment: Two de novo missense variants, p.(Leu333Ser) and p.(Arg313Gln), were identified in two unrelated probands with epilepsy. 1/2 had developmental delay. Whole-cell patch-clamp functional studies showed a significantly reduction in current amplitude and density.

Kcnj3-knockout mice display hyperactivity and decreased anxiety, while a knock-in mouse line displays spontaneous seizure-like activity.
Sources: Expert list
Mendeliome v1.1402 RNF213 Seb Lunke reviewed gene: RNF213: Rating: GREEN; Mode of pathogenicity: None; Publications: 37924258; Phenotypes: Leigh syndrome, MONDO:0009723, pediatric arterial ischemic stroke, MONDO:0018585, Moyamoya disease, MONDO:0016820; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1402 SEL1L Zornitza Stark Marked gene: SEL1L as ready
Mendeliome v1.1402 SEL1L Zornitza Stark Gene: sel1l has been classified as Green List (High Evidence).
Mendeliome v1.1402 PPID Elena Savva Marked gene: PPID as ready
Mendeliome v1.1402 PPID Elena Savva Gene: ppid has been classified as Red List (Low Evidence).
Mendeliome v1.1402 SEL1L Zornitza Stark Classified gene: SEL1L as Green List (high evidence)
Mendeliome v1.1402 SEL1L Zornitza Stark Gene: sel1l has been classified as Green List (High Evidence).
Mendeliome v1.1401 PLA2G16 Lauren Rogers changed review comment from: 7 patients from 4 unrelated consanguineous families with homozygous loss of function PTC variants. Features: 4/7 metabolic features, 6/7 neurological/skeletal features, 3/7 Psychomotor retardation/intellectual disability, 5/7 demyelinating peripheral neuropathy.

Null mouse and patient derived white adipose tissue showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in PPARγ. CRISPR–Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte diferentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ.
Sources: Literature; to: 7 patients from 4 unrelated consanguineous families with homozygous loss of function PTC variants. Features: 4/7 metabolic features, 6/7 neurological/skeletal features, 3/7 Psychomotor retardation/intellectual disability, 5/7 demyelinating peripheral neuropathy.

Null mouse and patient derived white adipose tissue showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in PPARγ. CRISPR–Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte differentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ.
Sources: Literature
Mendeliome v1.1401 MARK4 Rylee Peters changed review comment from: Missense variant, c.604T>C; p.Phe202Leu, identified in two siblings with childhood-onset neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and dysmorphic features. The variant is located in the catalytic domain of the kinase, and is inherited from unaffected mosaic mother.

Functional investigation revealed that the variant results in a gain-of-function in the ability of MARK4 to phosphorylate tau and leads to up-regulation of the mTORC1 pathway.
Sources: Literature; to: Heterozygous missense variant, c.604T>C; p.Phe202Leu, identified in two siblings with childhood-onset neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and dysmorphic features. The variant is located in the catalytic domain of the kinase, and is inherited from unaffected mosaic mother.

Functional investigation revealed that the variant results in a gain-of-function in the ability of MARK4 to phosphorylate tau and leads to up-regulation of the mTORC1 pathway.
Sources: Literature
Mendeliome v1.1401 PLA2G16 Lauren Rogers gene: PLA2G16 was added
gene: PLA2G16 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PLA2G16 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PLA2G16 were set to PMID: 37919452
Phenotypes for gene: PLA2G16 were set to Lipodystrophy (MONDO:0006573)
Review for gene: PLA2G16 was set to GREEN
Added comment: 7 patients from 4 unrelated consanguineous families with homozygous loss of function PTC variants. Features: 4/7 metabolic features, 6/7 neurological/skeletal features, 3/7 Psychomotor retardation/intellectual disability, 5/7 demyelinating peripheral neuropathy.

Null mouse and patient derived white adipose tissue showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in PPARγ. CRISPR–Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte diferentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ.
Sources: Literature
Mendeliome v1.1401 MARK4 Rylee Peters gene: MARK4 was added
gene: MARK4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MARK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MARK4 were set to PMID: 38041405
Phenotypes for gene: MARK4 were set to neurodevelopmental disorder (MONDO:0700092), MARK4-related
Mode of pathogenicity for gene: MARK4 was set to Other
Review for gene: MARK4 was set to AMBER
gene: MARK4 was marked as current diagnostic
Added comment: Missense variant, c.604T>C; p.Phe202Leu, identified in two siblings with childhood-onset neurodevelopmental disorder characterised by global developmental delay, intellectual disability, behavioural abnormalities, and dysmorphic features. The variant is located in the catalytic domain of the kinase, and is inherited from unaffected mosaic mother.

Functional investigation revealed that the variant results in a gain-of-function in the ability of MARK4 to phosphorylate tau and leads to up-regulation of the mTORC1 pathway.
Sources: Literature
Mendeliome v1.1401 SEL1L Sarah Pantaleo gene: SEL1L was added
gene: SEL1L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SEL1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEL1L were set to PMID: 37943610; PMID: 37943617
Phenotypes for gene: SEL1L were set to Neurodevelopmental disorder, MONDO:0700092, SEL1L-related
Penetrance for gene: SEL1L were set to Complete
Added comment: Wang paper PMID: 37943610

SEL1L protein is involved in the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation.

Report two biallelic missense variants in SEL1L in six children from three independent families presenting with developmental delay, intellectual disability, microcephaly, facial dysmorphisms, hypotonia and/or ataxia (termed ERAD-associated neurodevelopment disorder with onset in infancy (ENDI). The variants were hypomorphic and impaired ERAD function.

Identified by WES. Parents heterozygous and asymptomatic. P.(Gly585Asp) in Patient 1, p.(Met528Arg) in Patients 2 and 3 (siblings).

All variants cause substrate accumulation. The extent of substrate accumulation in knockin cells was modest compared to those in knockout cells, pointing to a hypomorphic nature.

They also had a variant in HRD1.



Weis paper PMID: 37943617

Third variant p.(Cys141Tyr), biallelic, causing premature death in five patients from a consanguineous family with early-onset neurodevelopmental disorders and agammaglobulinaemia due to severe SEL1L-HRD1 ERAD dysfunction.

This variant appears to have a more severe outcome, exhibiting B cell depletion and agammaglobulinaemia, causing the most severe dysfunction among all of the variants described by this group so far. They postulate that functionality of SEL1L-HRD1 ERAD is inversely correlated with disease severity in humans.

Their symptoms were dev delay, neurological disorder and agammaglobulinaemia in childhood. Along with severe axial hypotonia, short stature and microcephaly.

“Not a complete loss-of-function variant”.
Sources: Literature
Mendeliome v1.1401 FOXL1 Lilian Downie gene: FOXL1 was added
gene: FOXL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FOXL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXL1 were set to PMID: 34633540
Phenotypes for gene: FOXL1 were set to Otosclerosis 11 #MIM620576
Review for gene: FOXL1 was set to RED
Added comment: Single paper with variant in large AD family from Newfoundland with otosclerosis, hearing loss onset varied from late teens onwards. Segregation not completely convincing, 1 person with the deletion without otosclerosis. Conductive HL, sometimes mixed, not isolated SNHL. Second family with common haplotype and same 15bp deletion with otosclerosis. Functional studies. High population frequency and 3x homozygotes.
Sources: Literature
Mendeliome v1.1401 PPID Elena Savva gene: PPID was added
gene: PPID was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPID was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPID were set to 37977818
Phenotypes for gene: PPID were set to Stutter disorder, (MONDO:0000723), PPID-related
Review for gene: PPID was set to RED
Added comment: PMID: 37977818 - a large family (10 affected confirmed to have the variant) with stuttering/language disorder and a het missense (p.(Pro270Ser)). Mouse K/I model showed microstructural changes in the corticospinal tract
Sources: Literature
Mendeliome v1.1400 ACBD6 Lucy Spencer edited their review of gene: ACBD6: Added comment: PMID: 37951597
Much larger cohort with - 45 individuals from 28 families with a neurodevelopmental syndrome with complex and progressive movement disorder phenotype. 18 PTCs and splice, 1 missense 1 in frame insertion.

Phenotypes: weight was >50th percentile in 20/34 patients, all mod-severe GDD, facial dysmorphism in 38/40, mild cerebellar ataxia 35/41, limb spasticity/hypertonia 31/41, gait abnormalities in 33/35.; Changed publications: 37951597
Mendeliome v1.1400 PRPF19 Dean Phelan gene: PRPF19 was added
gene: PRPF19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRPF19 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRPF19 were set to PMID: 37962958
Phenotypes for gene: PRPF19 were set to Neurodevelopmental disorder (MONDO:0700092), PRPF19-related
Review for gene: PRPF19 was set to GREEN
Added comment: PMID: 37962958
Six unrelated individuals with de novo variants. Five had speech language motor delay, four had formal diagnosis of autism, three hypotonia and one fetus with multiple congenital abnormalities.
Sources: Literature
Mendeliome v1.1400 MGP Andrew Fennell reviewed gene: MGP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37675773; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1400 COL17A1 Zornitza Stark Phenotypes for gene: COL17A1 were changed from Epidermolysis bullosa, junctional 4, intermediate MIM#619787; Epithelial recurrent erosion dystrophy MIM#122400 to Epidermolysis bullosa, junctional 4, intermediate MIM#619787; Epithelial recurrent erosion dystrophy MIM#122400; Amelogenesis imperfecta MONDO:0019507, COL17A1-related
Mendeliome v1.1399 COL17A1 Zornitza Stark Publications for gene: COL17A1 were set to 27309958; 29708937; 25676728; 20301304
Mendeliome v1.1398 COL17A1 Zornitza Stark reviewed gene: COL17A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37979963; Phenotypes: Amelogenesis imperfecta MONDO:0019507, COL17A1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1398 GRIA3 Zornitza Stark Publications for gene: GRIA3 were set to 32977175; 17989220
Mendeliome v1.1397 GRIA3 Zornitza Stark Mode of inheritance for gene: GRIA3 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v1.1396 GRIA3 Zornitza Stark edited their review of gene: GRIA3: Added comment: New manuscript describing ~40 individuals with variants in GRIA3, including affected females. Some variants demonstrated to be LoF and others GoF. LoF variants generally caused a milder phenotype.; Changed publications: 32977175, 17989220, 38038360; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v1.1396 TRAPPC4 Zornitza Stark Phenotypes for gene: TRAPPC4 were changed from intellectual disability; epilepsy; spasticity; microcephaly to Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy, MIM# 618741
Mendeliome v1.1395 TRAPPC4 Zornitza Stark edited their review of gene: TRAPPC4: Changed phenotypes: Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy, MIM# 618741
Mendeliome v1.1395 WBP4 Zornitza Stark Publications for gene: WBP4 were set to
Mendeliome v1.1394 WBP4 Zornitza Stark reviewed gene: WBP4: Rating: GREEN; Mode of pathogenicity: None; Publications: 37963460; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, WBP4-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1394 MRPL39 Zornitza Stark Marked gene: MRPL39 as ready
Mendeliome v1.1394 MRPL39 Zornitza Stark Gene: mrpl39 has been classified as Green List (High Evidence).
Mendeliome v1.1394 MRPL39 Zornitza Stark Phenotypes for gene: MRPL39 were changed from Mitochondrial disease MONDO:0044970 to Combined oxidative phosphorylation deficiency-59 (COXPD59), MIM#620646
Mendeliome v1.1393 MRPL39 Zornitza Stark reviewed gene: MRPL39: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined oxidative phosphorylation deficiency-59 (COXPD59), MIM#620646; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1393 CNTN2 Zornitza Stark Classified gene: CNTN2 as Green List (high evidence)
Mendeliome v1.1393 CNTN2 Zornitza Stark Gene: cntn2 has been classified as Green List (High Evidence).
Mendeliome v1.1392 CNTN2 Zornitza Stark Publications for gene: CNTN2 were set to 23518707; 34120799; 34691156
Mendeliome v1.1391 CNTN2 Zornitza Stark edited their review of gene: CNTN2: Added comment: Additional family, consanguineous, homozygous variants segregated in 3 affected sibs and was not homozygous in unaffected sib. Seizures later childhood onset and mild ID.; Changed rating: GREEN; Changed publications: 23518707, 37359369; Changed phenotypes: Epilepsy, MONDO:0015653, CNTN2-related
Mendeliome v1.1391 FA2H Zornitza Stark Publications for gene: FA2H were set to 29423566
Mendeliome v1.1390 FA2H Zornitza Stark edited their review of gene: FA2H: Changed publications: 29423566, 31135052, 18463364, 19068277, 20104589
Mendeliome v1.1390 FA2H Zornitza Stark changed review comment from: Well established gene-disease association, both peripheral and central features (dystonia, dysarthria, cognitive impairment, and epilepsy), childhood-onset, progressive.
Sources: Expert Review; to: Well established gene-disease association, both peripheral and central features (dystonia, dysarthria, cognitive impairment, and epilepsy), childhood-onset, progressive.

PubMed: 31135052 – 19 patients from 16 families consistent with a complicated form of SPG.
PubMed:18463364 – 7 individuals identified from a large consanguineous family with SPG.
PubMed: 19068277 – 7 patients from 2 unrelated consanguineous middle eastern families
PubMed: 20104589– Multiple affected individuals in an Omani family. Findings indicated that an abnormal hydroxylation of myelin galactocerebroside lipid components can lead to the progression of a severe phenotype.

Sources: Expert Review
Mendeliome v1.1390 FA2H Zornitza Stark Marked gene: FA2H as ready
Mendeliome v1.1390 FA2H Zornitza Stark Gene: fa2h has been classified as Green List (High Evidence).
Mendeliome v1.1390 FA2H Zornitza Stark Classified gene: FA2H as Green List (high evidence)
Mendeliome v1.1390 FA2H Zornitza Stark Gene: fa2h has been classified as Green List (High Evidence).
Mendeliome v1.1389 FA2H Zornitza Stark gene: FA2H was added
gene: FA2H was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FA2H was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FA2H were set to 29423566
Phenotypes for gene: FA2H were set to Spastic paraplegia 35, autosomal recessive, MIM#611026
Review for gene: FA2H was set to GREEN
Added comment: Well established gene-disease association, both peripheral and central features (dystonia, dysarthria, cognitive impairment, and epilepsy), childhood-onset, progressive.
Sources: Expert Review
Mendeliome v1.1388 EFCAB1 Zornitza Stark Tag new gene name tag was added to gene: EFCAB1.
Mendeliome v1.1388 EFCAB1 Zornitza Stark Phenotypes for gene: EFCAB1 were changed from Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related to Ciliary dyskinesia, primary, 53, MIM# 620642
Mendeliome v1.1387 EFCAB1 Zornitza Stark edited their review of gene: EFCAB1: Added comment: Ciliary dyskinesia, primary, 53, MIM# 620642; Changed phenotypes: Ciliary dyskinesia, primary, 53, MIM# 620642
Mendeliome v1.1387 WNK3 Zornitza Stark Phenotypes for gene: WNK3 were changed from Neurodevelopmental disorder, WNK3-related (MONDO#0700092) to Prieto syndrome, MIM# 309610
Mendeliome v1.1386 WNK3 Zornitza Stark edited their review of gene: WNK3: Changed phenotypes: Prieto syndrome, MIM# 309610
Mendeliome v1.1386 PHLDB1 Zornitza Stark Phenotypes for gene: PHLDB1 were changed from osteogenesis imperfecta, MONDO:0019019 to Osteogenesis imperfecta, type XXIII, MIM# 620639
Mendeliome v1.1385 PHLDB1 Zornitza Stark reviewed gene: PHLDB1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Osteogenesis imperfecta, type XXIII, MIM# 620639; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1385 FLII Zornitza Stark Phenotypes for gene: FLII were changed from Dilated cardiomyopathy MONDO:0005021 to Cardiomyopathy, dilated, 2J, MIM# 620635
Mendeliome v1.1384 FLII Zornitza Stark edited their review of gene: FLII: Changed phenotypes: Cardiomyopathy, dilated, 2J, MIM# 620635
Mendeliome v1.1384 RNF31 Zornitza Stark Phenotypes for gene: RNF31 were changed from Immune deficiency; Autoinflammation to Immunodeficiency 115 with autoinflammation, MIM# 620632
Mendeliome v1.1383 RNF31 Zornitza Stark edited their review of gene: RNF31: Changed phenotypes: Immunodeficiency 115 with autoinflammation, MIM# 620632
Mendeliome v1.1383 KDR Zornitza Stark Phenotypes for gene: KDR were changed from Pulmonary hypertension; Haemangioma, capillary infantile, somatic 602089 to Pulmonary hypertension; Haemangioma, capillary infantile, somatic 602089; Tetralogy of Fallot, MONDO:0008542
Mendeliome v1.1382 KDR Zornitza Stark Mode of inheritance for gene: KDR was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1381 KDR Zornitza Stark edited their review of gene: KDR: Added comment: PMID 34113005: Exome sequencing in a family with two siblings affected by ToF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants.

Rare variant burden analysis conducted in a set of 1,569 patients of European descent with ToF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 × 10-11). At this stage MOI unclear and insufficient evidence for either MOI.; Changed publications: 31980491, 29650961, 18931684, 34113005; Changed phenotypes: Pulmonary hypertension, Haemangioma, capillary infantile, somatic 602089, Tetralogy of Fallot, MONDO:0008542; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1381 DOT1L Zornitza Stark Marked gene: DOT1L as ready
Mendeliome v1.1381 DOT1L Zornitza Stark Gene: dot1l has been classified as Green List (High Evidence).
Mendeliome v1.1381 DOT1L Zornitza Stark Classified gene: DOT1L as Green List (high evidence)
Mendeliome v1.1381 DOT1L Zornitza Stark Gene: dot1l has been classified as Green List (High Evidence).
Mendeliome v1.1380 DOT1L Zornitza Stark gene: DOT1L was added
gene: DOT1L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DOT1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DOT1L were set to 37827158
Phenotypes for gene: DOT1L were set to Neurodevelopmental disorder, MONDO:0700092, DOT1L-related
Mode of pathogenicity for gene: DOT1L was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: DOT1L was set to GREEN
Added comment: Nine individuals reported with seven de novo missense variants.

All had DD/ID and variable patterns of associated congenital anomalies.

Variants demonstrated to be GoF and lead to increased H3K79 methylation levels in flies and human cells.
Sources: Literature
Mendeliome v1.1379 UNC119 Zornitza Stark Classified gene: UNC119 as Amber List (moderate evidence)
Mendeliome v1.1379 UNC119 Zornitza Stark Gene: unc119 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1378 UNC119 Zornitza Stark changed review comment from: Immunodeficiency 13: Single case reported with the missense Gly22Val. The allele frequency of this variant is >2% in the African/African American subpopulation in gnomAD v2.1, including 6 homozygotes. RED for this association.

Borderline Green for association with cone-rod dystrophy.; to: Immunodeficiency 13: Single case reported with the missense Gly22Val. The allele frequency of this variant is >2% in the African/African American subpopulation in gnomAD v2.1, including 6 homozygotes. RED for this association.

Cone-rod dystrophy: one of the reported variants is missense with no other supporting evidence.
Mendeliome v1.1378 UNC119 Zornitza Stark edited their review of gene: UNC119: Changed rating: AMBER
Mendeliome v1.1378 MECR Zornitza Stark Phenotypes for gene: MECR were changed from Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, MIM# 617282; MONDO:0015003 to Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, MIM# 617282; MONDO:0015003; Optic atrophy 16, MIM# 620629
Mendeliome v1.1377 MECR Zornitza Stark edited their review of gene: MECR: Changed phenotypes: Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, MIM# 617282, MONDO:0015003, Optic atrophy 16, MIM# 620629
Mendeliome v1.1377 THOC6 Ling Sun Deleted their review
Mendeliome v1.1377 THOC6 Ling Sun Deleted their comment
Mendeliome v1.1377 ARPC5 Zornitza Stark Phenotypes for gene: ARPC5 were changed from Combined immunodeficiency, ARPC5-related MONDO:0015131 to Immunodeficiency 133 with autoimmunity and autoinflammation, MIM# 620565
Mendeliome v1.1376 ARPC5 Zornitza Stark commented on gene: ARPC5: Features of autoinflammation common: haemolytic anaemia, thrombocytopenia, hepatosplenomegaly, leukocytosis, neutrophilia, and elevated acute phase reactants. More variable systemic features may include coeliac disease or enteropathy, ileus, nephropathy, eczema, and dermatomyositis.
Mendeliome v1.1376 ARPC5 Zornitza Stark reviewed gene: ARPC5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 133 with autoimmunity and autoinflammation, MIM# 620565; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1376 RRAGC Zornitza Stark Publications for gene: RRAGC were set to 27234373
Mendeliome v1.1375 RRAGC Zornitza Stark Phenotypes for gene: RRAGC were changed from Dilated cardiomyopathy (MONDO:0005021), RRAGC-related to Long-Olsen syndrome, MIM# 620609
Mendeliome v1.1374 SLCO1B3 Zornitza Stark Publications for gene: SLCO1B3 were set to 33860121
Mendeliome v1.1373 SLCO1B3 Zornitza Stark Classified gene: SLCO1B3 as Green List (high evidence)
Mendeliome v1.1373 SLCO1B3 Zornitza Stark Gene: slco1b3 has been classified as Green List (High Evidence).
Mendeliome v1.1372 SLCO1B3 Zornitza Stark edited their review of gene: SLCO1B3: Added comment: Five additional individuals reported.; Changed rating: GREEN; Changed publications: 33860121, 36964102
Mendeliome v1.1372 SLCO1B1 Zornitza Stark Publications for gene: SLCO1B1 were set to 30250148; 24918167; 33860121
Mendeliome v1.1371 SLCO1B1 Zornitza Stark edited their review of gene: SLCO1B1: Changed publications: 36964102, 33860121
Mendeliome v1.1371 SLCO1B1 Zornitza Stark Classified gene: SLCO1B1 as Green List (high evidence)
Mendeliome v1.1371 SLCO1B1 Zornitza Stark Gene: slco1b1 has been classified as Green List (High Evidence).
Mendeliome v1.1370 SLCO1B1 Zornitza Stark edited their review of gene: SLCO1B1: Changed rating: GREEN
Mendeliome v1.1370 SLCO1B1 Zornitza Stark edited their review of gene: SLCO1B1: Added comment: Five additional individuals reported.; Changed publications: 33860121, 33860121
Mendeliome v1.1370 KCNA3 Zornitza Stark Publications for gene: KCNA3 were set to
Mendeliome v1.1369 KCNA3 Zornitza Stark reviewed gene: KCNA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 37964487; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, KCNA3-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1369 ERG Zornitza Stark Phenotypes for gene: ERG were changed from primary lymphoedema MONDO#0019175, ERG-related to Lymphatic malformation 14, MIM# 620602
Mendeliome v1.1368 PLS3 Zornitza Stark Phenotypes for gene: PLS3 were changed from Bone mineral density QTL18, osteoporosis - MIM#300910; congenital diaphragmatic hernia MONDO:0005711, PLS3-related to Bone mineral density QTL18, osteoporosis - MIM#300910; Diaphragmatic hernia 5, X-linked, MIM# 306950
Mendeliome v1.1367 PLS3 Zornitza Stark edited their review of gene: PLS3: Changed phenotypes: Bone mineral density QTL18, osteoporosis - MIM#300910, Diaphragmatic hernia 5, X-linked, MIM# 306950
Mendeliome v1.1367 TOMM7 Zornitza Stark Phenotypes for gene: TOMM7 were changed from Inborn mitochondrial disorder MONDO:0004069, TOMM7-related to Garg-Mishra progeroid syndrome, MIM# 620601
Mendeliome v1.1366 TOMM7 Zornitza Stark edited their review of gene: TOMM7: Changed phenotypes: Garg-Mishra progeroid syndrome, MIM# 620601
Mendeliome v1.1366 MCAT Zornitza Stark Phenotypes for gene: MCAT were changed from Leber hereditary optic neuropathy, autosomal recessive, MONDO:0030309 to Optic atrophy 15, MIM# 620583
Mendeliome v1.1365 MCAT Zornitza Stark Publications for gene: MCAT were set to 31915829
Mendeliome v1.1364 MCAT Zornitza Stark edited their review of gene: MCAT: Added comment: Second individual reported in PMID 33918393; Changed publications: 33918393
Mendeliome v1.1364 MCAT Zornitza Stark edited their review of gene: MCAT: Changed phenotypes: Optic atrophy 15, MIM# 620583
Mendeliome v1.1364 MDM4 Bryony Thompson Marked gene: MDM4 as ready
Mendeliome v1.1364 MDM4 Bryony Thompson Gene: mdm4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1364 MDM4 Bryony Thompson Classified gene: MDM4 as Amber List (moderate evidence)
Mendeliome v1.1364 MDM4 Bryony Thompson Gene: mdm4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1363 MDM4 Bryony Thompson gene: MDM4 was added
gene: MDM4 was added to Mendeliome. Sources: Other
Mode of inheritance for gene: MDM4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MDM4 were set to 32300648; 33104793
Phenotypes for gene: MDM4 were set to bone marrow failure syndrome MONDO:0000159, MDM4-related
Review for gene: MDM4 was set to AMBER
Added comment: A single family was reported to segregate a missense variant (p.Thr454Met) with features suggestive of dyskeratosis congenita, e.g., bone marrow hypocellularity, short telomeres, tongue squamous cell carcinoma, and acute myeloid leukemia. A mouse model of p.Thr454Met showed increased p53 activity, decreased telomere length, and bone marrow failure.
Sources: Other
Mendeliome v1.1362 THOC6 Ling Sun changed review comment from: THOC6 homozygous or compound heterozygous variants are associated with Beaulieu-Boycott-Innes syndrome. Clinical spectrum is heterogenous, with major phenotype DD and ID (Note that this gene is already on the ID panel). Some are affected with structural cardiac anomalies, therefore not all individuals with BBIS have cardiac anomalies (hence, not a major phenotype).

PMID 35426486: Two siblings with maternally inherited c.[298T>A;700G>T;824G>A], p.[(Trp100Arg);(Val234Leu);(Gly275Asp)] and paternally inherited c.977T>G, p.(Val326Gly) [compound het]

PMID: 30476144: A boy with mat UPD homozygous c.(298T>A; 700G>C; 824G>C)
A girl with maternally inherited c.(298T>A, 700G>C, 824G>A) and paternally inherited c.569G>A, p.(Gly190Glu) [compount het]

PMID: 32282736: A boy with paternally inherited c.664T>C (p.Trp222Arg) and maternally inherited c.945+1 G>A [compound het]; to: THOC6 homozygous or compound heterozygous variants are associated with Beaulieu-Boycott-Innes syndrome. Clinical spectrum is heterogenous, with major phenotype DD and ID (Note that this gene is already on the ID panel). Some are affected with structural cardiac anomalies, therefore not all individuals with BBIS have cardiac anomalies (hence, not a major phenotype, eg. see https://databases.lovd.nl/shared/diseases/03390).

PMID 35426486: Two siblings with maternally inherited c.[298T>A;700G>T;824G>A], p.[(Trp100Arg);(Val234Leu);(Gly275Asp)] and paternally inherited c.977T>G, p.(Val326Gly) [compound het]

PMID: 30476144: A boy with mat UPD homozygous c.(298T>A; 700G>C; 824G>C)
A girl with maternally inherited c.(298T>A, 700G>C, 824G>A) and paternally inherited c.569G>A, p.(Gly190Glu) [compount het]

PMID: 32282736: A boy with paternally inherited c.664T>C (p.Trp222Arg) and maternally inherited c.945+1 G>A [compound het]
Mendeliome v1.1362 THOC6 Ling Sun changed review comment from: THOC6 homozygous or compound heterozygous variants are associated with Beaulieu-Boycott-Innes syndrome. Clinical spectrum is heterogenous, with major phenotype DD and ID (Note that this gene is already on the ID panel). Some are affected with structural cardiac anomalies, therefore not all individuals with BBIS have cardiac anomalies (hence, not a major phenotype).

PMID 35426486: Two siblings with maternally inherited c.[298T>A;700G>T;824G>A], p.[(Trp100Arg);(Val234Leu);(Gly275Asp)] and paternally inherited c.977T>G, p.(Val326Gly)

PMID: 30476144: A boy with mat UPD homozygous c.(298T>A; 700G>C; 824G>C)
A girl with maternally inherited c.(298T>A, 700G>C, 824G>A) and paternally inherited c.569G>A, p.(Gly190Glu); to: THOC6 homozygous or compound heterozygous variants are associated with Beaulieu-Boycott-Innes syndrome. Clinical spectrum is heterogenous, with major phenotype DD and ID (Note that this gene is already on the ID panel). Some are affected with structural cardiac anomalies, therefore not all individuals with BBIS have cardiac anomalies (hence, not a major phenotype).

PMID 35426486: Two siblings with maternally inherited c.[298T>A;700G>T;824G>A], p.[(Trp100Arg);(Val234Leu);(Gly275Asp)] and paternally inherited c.977T>G, p.(Val326Gly) [compound het]

PMID: 30476144: A boy with mat UPD homozygous c.(298T>A; 700G>C; 824G>C)
A girl with maternally inherited c.(298T>A, 700G>C, 824G>A) and paternally inherited c.569G>A, p.(Gly190Glu) [compount het]

PMID: 32282736: A boy with paternally inherited c.664T>C (p.Trp222Arg) and maternally inherited c.945+1 G>A [compound het]
Mendeliome v1.1362 THOC6 Ling Sun changed review comment from: THOC6 homozygous or compound heterozygous variants are associated with Beaulieu-Boycott-Innes syndrome. Clinical spectrum is heterogenous, with major phenotype DD and ID (Note that this gene is already on the ID panel). Some are affected with structural cardiac anomalies (syndromic phenotype).

PMID 35426486: Two siblings with maternally inherited c.[298T>A;700G>T;824G>A], p.[(Trp100Arg);(Val234Leu);(Gly275Asp)] and paternally inherited c.977T>G, p.(Val326Gly)

PMID: 30476144: A boy with mat UPD homozygous c.(298T>A; 700G>C; 824G>C)
A girl with maternally inherited c.(298T>A, 700G>C, 824G>A) and paternally inherited c.569G>A, p.(Gly190Glu); to: THOC6 homozygous or compound heterozygous variants are associated with Beaulieu-Boycott-Innes syndrome. Clinical spectrum is heterogenous, with major phenotype DD and ID (Note that this gene is already on the ID panel). Some are affected with structural cardiac anomalies, therefore not all individuals with BBIS have cardiac anomalies (hence, not a major phenotype).

PMID 35426486: Two siblings with maternally inherited c.[298T>A;700G>T;824G>A], p.[(Trp100Arg);(Val234Leu);(Gly275Asp)] and paternally inherited c.977T>G, p.(Val326Gly)

PMID: 30476144: A boy with mat UPD homozygous c.(298T>A; 700G>C; 824G>C)
A girl with maternally inherited c.(298T>A, 700G>C, 824G>A) and paternally inherited c.569G>A, p.(Gly190Glu)
Mendeliome v1.1362 THOC6 Ling Sun reviewed gene: THOC6: Rating: AMBER; Mode of pathogenicity: None; Publications: 35426486, 30476144; Phenotypes: VSD/ASD, severe aortic and left ventricular hypoplasia, Mild dilation of the right chambers and a mild myocardial hypertrophy secondary to a chronic hypertension, ventriculomegaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1362 TCIRG1 Zornitza Stark edited their review of gene: TCIRG1: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1362 DAW1 Zornitza Stark Phenotypes for gene: DAW1 were changed from Primary ciliary dyskinesia, MONDO:0016575; Visceral heterotaxy, MONDO:0018677 to Primary ciliary dyskinesia, with or without heterotaxy, MIM#620570
Mendeliome v1.1361 DAW1 Zornitza Stark reviewed gene: DAW1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia, with or without heterotaxy, MIM#620570; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1361 TCIRG1 Achchuthan Shanmugasundram reviewed gene: TCIRG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24753205, 35573728; Phenotypes: severe congenital neutropenia, MONDO:0018542; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1361 TUBGCP2 Zornitza Stark Phenotypes for gene: TUBGCP2 were changed from Lissencephaly; pachygyria; subcortical band heterotopia; microcephaly; intellectual disability to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, OMIM # 618737; Lissencephaly; pachygyria; subcortical band heterotopia; microcephaly; intellectual disability
Mendeliome v1.1360 TUBGCP2 Zornitza Stark edited their review of gene: TUBGCP2: Changed phenotypes: Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, OMIM # 618737, Lissencephaly, pachygyria, subcortical band heterotopia, microcephaly, intellectual disability
Mendeliome v1.1360 PSMB10 Zornitza Stark Publications for gene: PSMB10 were set to 31783057
Mendeliome v1.1359 PSMB10 Zornitza Stark Classified gene: PSMB10 as Green List (high evidence)
Mendeliome v1.1359 PSMB10 Zornitza Stark Gene: psmb10 has been classified as Green List (High Evidence).
Mendeliome v1.1358 PSMB10 Zornitza Stark edited their review of gene: PSMB10: Added comment: PMID 37600812: 3 additional unrelated patients with compound heterozygous variants with structural modelling of proteasome assembly.; Changed rating: GREEN; Changed publications: 31783057, 37600812
Mendeliome v1.1358 FYB1 Zornitza Stark Marked gene: FYB1 as ready
Mendeliome v1.1358 FYB1 Zornitza Stark Gene: fyb1 has been classified as Green List (High Evidence).
Mendeliome v1.1358 FYB1 Zornitza Stark Classified gene: FYB1 as Green List (high evidence)
Mendeliome v1.1358 FYB1 Zornitza Stark Gene: fyb1 has been classified as Green List (High Evidence).
Mendeliome v1.1357 FYB1 Zornitza Stark gene: FYB1 was added
gene: FYB1 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: FYB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FYB1 were set to 25516138; 25876182
Phenotypes for gene: FYB1 were set to Thrombocytopenia 3, MIM# 273900
Review for gene: FYB1 was set to GREEN
Added comment: Two families with LoF variants and segregation reported in the literature. Aware of two additional cases through clinical testing (Prevention Genetics).

Good functional evidence, including mouse models.

Moderate by ClinGen, though note score was in 'Strong' range and downgraded due to two families in the literature only.
Sources: Expert Review
Mendeliome v1.1356 MCTS1 Zornitza Stark Marked gene: MCTS1 as ready
Mendeliome v1.1356 MCTS1 Zornitza Stark Gene: mcts1 has been classified as Green List (High Evidence).
Mendeliome v1.1356 MCTS1 Zornitza Stark Classified gene: MCTS1 as Green List (high evidence)
Mendeliome v1.1356 MCTS1 Zornitza Stark Gene: mcts1 has been classified as Green List (High Evidence).
Mendeliome v1.1355 MCTS1 Zornitza Stark gene: MCTS1 was added
gene: MCTS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MCTS1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: MCTS1 were set to 37875108
Phenotypes for gene: MCTS1 were set to Inherited susceptibility to mycobacterial diseases, MONDO:0019146, MCTS1-related
Review for gene: MCTS1 was set to GREEN
Added comment: 6 male subjects from 5 kindreds with LOF MCTS-1 variants with MSMD.
Extensive ex-vivo functional validation and mouse model.
Sources: Literature
Mendeliome v1.1354 DLG2 Zornitza Stark Tag SV/CNV tag was added to gene: DLG2.
Mendeliome v1.1354 SGSM3 Zornitza Stark Tag founder tag was added to gene: SGSM3.
Mendeliome v1.1354 SGSM3 Zornitza Stark Marked gene: SGSM3 as ready
Mendeliome v1.1354 SGSM3 Zornitza Stark Gene: sgsm3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1354 SGSM3 Zornitza Stark Classified gene: SGSM3 as Amber List (moderate evidence)
Mendeliome v1.1354 SGSM3 Zornitza Stark Gene: sgsm3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1353 FMNL2 Zornitza Stark Marked gene: FMNL2 as ready
Mendeliome v1.1353 FMNL2 Zornitza Stark Gene: fmnl2 has been classified as Red List (Low Evidence).
Mendeliome v1.1353 FMNL2 Zornitza Stark Phenotypes for gene: FMNL2 were changed from inflammatory bowel disease, MONDO:0005265 to inflammatory bowel disease, MONDO:0005265, FMNL2-related
Mendeliome v1.1352 FMNL2 Zornitza Stark Classified gene: FMNL2 as Red List (low evidence)
Mendeliome v1.1352 FMNL2 Zornitza Stark Gene: fmnl2 has been classified as Red List (Low Evidence).
Mendeliome v1.1351 FMNL2 Achchuthan Shanmugasundram gene: FMNL2 was added
gene: FMNL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FMNL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FMNL2 were set to 34043722
Phenotypes for gene: FMNL2 were set to inflammatory bowel disease, MONDO:0005265
Mode of pathogenicity for gene: FMNL2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: FMNL2 was set to AMBER
Added comment: A patient was reported with a de novo heterozygous FMNL2 variant (p.Leu136Pro) and with severe very early onset inflammatory bowel disease (IBD). The functional characterisation of this variant showed that FMNL2 L136P protein displayed subcellular mislocalisation and deregulated protein autoinhibition indicating gain-of-function mechanism (PMID:34043722).
Sources: Literature
Mendeliome v1.1351 HIST1H4J Zornitza Stark Publications for gene: HIST1H4J were set to 31804630
Mendeliome v1.1350 HIST1H4J Zornitza Stark Marked gene: HIST1H4J as ready
Mendeliome v1.1350 HIST1H4J Zornitza Stark Added comment: Comment when marking as ready: New gene name: H4C11
Mendeliome v1.1350 HIST1H4J Zornitza Stark Gene: hist1h4j has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1350 HIST1H4J Zornitza Stark Tag new gene name tag was added to gene: HIST1H4J.
Mendeliome v1.1350 HIST1H4I Zornitza Stark Marked gene: HIST1H4I as ready
Mendeliome v1.1350 HIST1H4I Zornitza Stark Added comment: Comment when marking as ready: New gene name: H4C9
Mendeliome v1.1350 HIST1H4I Zornitza Stark Gene: hist1h4i has been classified as Green List (High Evidence).
Mendeliome v1.1350 HIST1H4I Zornitza Stark Tag new gene name tag was added to gene: HIST1H4I.
Mendeliome v1.1350 HIST1H4F Zornitza Stark Marked gene: HIST1H4F as ready
Mendeliome v1.1350 HIST1H4F Zornitza Stark Added comment: Comment when marking as ready: New gene name H4C6
Mendeliome v1.1350 HIST1H4F Zornitza Stark Gene: hist1h4f has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1350 HIST1H4F Zornitza Stark Tag new gene name tag was added to gene: HIST1H4F.
Mendeliome v1.1350 HIST1H4D Zornitza Stark Marked gene: HIST1H4D as ready
Mendeliome v1.1350 HIST1H4D Zornitza Stark Added comment: Comment when marking as ready: New gene name H4C4
Mendeliome v1.1350 HIST1H4D Zornitza Stark Gene: hist1h4d has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1350 HIST1H4D Zornitza Stark Tag new gene name tag was added to gene: HIST1H4D.
Mendeliome v1.1350 HIST1H4C Zornitza Stark Tag new gene name tag was added to gene: HIST1H4C.
Mendeliome v1.1350 CCDC66 Ain Roesley Phenotypes for gene: CCDC66 were changed from to myopia MONDO:0001384, CCDC66-related
Mendeliome v1.1349 CCDC66 Ain Roesley Classified gene: CCDC66 as Red List (low evidence)
Mendeliome v1.1349 CCDC66 Ain Roesley Gene: ccdc66 has been classified as Red List (Low Evidence).
Mendeliome v1.1348 CCDC66 Ain Roesley Marked gene: CCDC66 as ready
Mendeliome v1.1348 CCDC66 Ain Roesley Added comment: Comment when marking as ready: de novo NMD in another family
5 other de novo missense (D94E absent in nomad, T121A 25 hets, R499C 31 hets, R553Q 59 hets, K803E 40 hets)

noted that there's lots of NMD variants in gnomad v4
Mendeliome v1.1348 CCDC66 Ain Roesley Gene: ccdc66 has been removed from the panel.
Mendeliome v1.1348 MYO9B Elena Savva Phenotypes for gene: MYO9B were changed from {Celiac disease, susceptibility to, 4} MIM#609753 to Charcot-Marie-Tooth disease type 2 (MONDO:0018993), MYO9B-related
Mendeliome v1.1347 MYO9B Elena Savva Mode of inheritance for gene: MYO9B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1346 MYO9B Elena Savva Classified gene: MYO9B as Amber List (moderate evidence)
Mendeliome v1.1346 MYO9B Elena Savva Gene: myo9b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1345 MYO9B Melanie Marty reviewed gene: MYO9B: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36260368; Phenotypes: Charcot-Marie-Tooth disease type 2 (MONDO:0018993), MYO9B-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1345 MAN2B2 Zornitza Stark Phenotypes for gene: MAN2B2 were changed from Congenital disorder of glycosylation; immunodeficiency to Congenital disorder of glycosylation, MONDO:0015286, MAN2B2-related; immunodeficiency
Mendeliome v1.1344 HEPHL1 Ain Roesley Marked gene: HEPHL1 as ready
Mendeliome v1.1344 HEPHL1 Ain Roesley Gene: hephl1 has been classified as Red List (Low Evidence).
Mendeliome v1.1344 HEPHL1 Ain Roesley Classified gene: HEPHL1 as Red List (low evidence)
Mendeliome v1.1344 HEPHL1 Ain Roesley Gene: hephl1 has been classified as Red List (Low Evidence).
Mendeliome v1.1343 MIEF1 Seb Lunke Marked gene: MIEF1 as ready
Mendeliome v1.1343 MIEF1 Seb Lunke Gene: mief1 has been classified as Red List (Low Evidence).
Mendeliome v1.1343 ELP1 Ain Roesley Phenotypes for gene: ELP1 were changed from Dysautonomia, familial MIM#223900; paediatric medulloblastoma to Dysautonomia, familial MIM#223900; paediatric medulloblastoma; neurodevelopmental disorder, MONDO:0700092, ELP1-related
Mendeliome v1.1342 ELP1 Ain Roesley Publications for gene: ELP1 were set to 11179008; 32296180
Mendeliome v1.1341 MAN2B2 Zornitza Stark Publications for gene: MAN2B2 were set to 31775018
Mendeliome v1.1340 ELP1 Ain Roesley reviewed gene: ELP1: Rating: RED; Mode of pathogenicity: None; Publications: 36864284; Phenotypes: neurodevelopmental disorder, MONDO:0700092, ELP1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1340 CCDC66 Anna Ritchie gene: CCDC66 was added
gene: CCDC66 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC66 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CCDC66 were set to PMID: 37852749
Review for gene: CCDC66 was set to RED
Added comment: Nonsense variant (c.172C>T, p.Q58X) segregating in family with 5 affected members with high myopia (HM). Additionally, one family member with the variant displayed no symptoms, hinting at possible incomplete penetrance. Six other rare variants were identified in 200 sporadic high myopia patients that could potentially be linked to HM. A deficiency in CCDC66 might disrupt cell proliferation by influencing the mitotic process during retinal growth, leading to HM.
Sources: Literature
Mendeliome v1.1340 MAN2B2 Zornitza Stark Classified gene: MAN2B2 as Amber List (moderate evidence)
Mendeliome v1.1340 MAN2B2 Zornitza Stark Gene: man2b2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1339 AGPAT3 Elena Savva Classified gene: AGPAT3 as Amber List (moderate evidence)
Mendeliome v1.1339 AGPAT3 Elena Savva Gene: agpat3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1339 MIEF1 Seb Lunke Classified gene: MIEF1 as Red List (low evidence)
Mendeliome v1.1339 MIEF1 Seb Lunke Added comment: Comment on list classification: Two patients but both missense and one with a few too many hets. Functional data not quite strong enough.
Mendeliome v1.1339 MIEF1 Seb Lunke Gene: mief1 has been classified as Red List (Low Evidence).
Mendeliome v1.1338 AGPAT3 Elena Savva Marked gene: AGPAT3 as ready
Mendeliome v1.1338 AGPAT3 Elena Savva Gene: agpat3 has been removed from the panel.
Mendeliome v1.1338 SGSM3 Dean Phelan gene: SGSM3 was added
gene: SGSM3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SGSM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGSM3 were set to PMID: 37833060
Phenotypes for gene: SGSM3 were set to Neurodevelopmental disorder (MONDO:0700092), SGSM3-related
Review for gene: SGSM3 was set to AMBER
Added comment: PMID: 37833060
- 13 patients from 8 families of Ashkenazi Jewish origin all had the same homozygous frameshift variant (c.981dup). Predicted to cause NMD. The variant co-segregated with disease in all available family members. The affected individuals displayed mild global developmental delay and mild to moderate intellectual disability. Additional prevalent phenotypes observed included hypotonia, behavioural challenges and short stature. Considered a founder variant (1 in 52 Ashkenazi Jews carry the variant). Also present in other populations but no homozygotes in gnomAD.
Sources: Literature
Mendeliome v1.1338 LRRC23 Elena Savva Phenotypes for gene: LRRC23 were changed from Non-syndromic male infertility due to sperm motility disorder, (MONDO:0017173), LRRC23-related to Non-syndromic male infertility due to sperm motility disorder, (MONDO:0017173), LRRC23-related
Mendeliome v1.1337 LRRC23 Elena Savva Marked gene: LRRC23 as ready
Mendeliome v1.1337 LRRC23 Elena Savva Gene: lrrc23 has been classified as Red List (Low Evidence).
Mendeliome v1.1337 LRRC23 Elena Savva Phenotypes for gene: LRRC23 were changed from Non-syndromic male infertility due to sperm motility disorder MONDO:0017173 to Non-syndromic male infertility due to sperm motility disorder, (MONDO:0017173), LRRC23-related
Mendeliome v1.1336 LRRC23 Elena Savva Classified gene: LRRC23 as Red List (low evidence)
Mendeliome v1.1336 LRRC23 Elena Savva Gene: lrrc23 has been classified as Red List (Low Evidence).
Mendeliome v1.1335 AGPAT3 Ee Ming Wong gene: AGPAT3 was added
gene: AGPAT3 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: AGPAT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGPAT3 were set to 37821758
Phenotypes for gene: AGPAT3 were set to Neurodevelopmental disorder (MONDO#0700092), AGPAT3-related
Review for gene: AGPAT3 was set to GREEN
gene: AGPAT3 was marked as current diagnostic
Added comment: - Single consanguineous family with four individuals with severe intellectual disability and retinitis pigmentosa
- All affected individuals were homozygous for a nonsense variant in AGPAT3, healthy unaffected individuals who were tested were heterozygous for the variant
- Overexpression of mutant transcript revealed absence of AGPAT3 protein compared to WT transcript via Western blot analysis
- KO AGPAT3 mouse demonstrated impaired neuronal migration
Sources: Literature
Mendeliome v1.1335 HEPHL1 Naomi Baker gene: HEPHL1 was added
gene: HEPHL1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HEPHL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEPHL1 were set to PMID: 31125343; 31293895
Phenotypes for gene: HEPHL1 were set to Abnormal hair, joint laxity, and developmental delay (MIM#261990)
Review for gene: HEPHL1 was set to RED
Added comment: PMID: 31125343 - Single patient reported with biallelic variants (missense and splice) that presented with abnormal hair and early cognitive delays. Authors also created a knockout mouse, with homozygotes having short, curled whiskers while heterozygotes did not have this phenotype.

PMID: 31293895 - Report of curly whiskers (cw) mouse model that has a spontaneous variant (frame shifting single base insertion) in Hephl1.
Sources: Literature
Mendeliome v1.1335 CD81 Zornitza Stark Publications for gene: CD81 were set to 20237408
Mendeliome v1.1334 DLG2 Elena Savva Marked gene: DLG2 as ready
Mendeliome v1.1334 DLG2 Elena Savva Gene: dlg2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1334 DLG2 Elena Savva Classified gene: DLG2 as Amber List (moderate evidence)
Mendeliome v1.1334 DLG2 Elena Savva Gene: dlg2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1333 DLG2 Elena Savva gene: DLG2 was added
gene: DLG2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DLG2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DLG2 were set to PMID: 37860969
Phenotypes for gene: DLG2 were set to Intellectual disability (MONDO#0001071), DLG2-related
Review for gene: DLG2 was set to AMBER
Added comment: PMID: 37860969 - 13 patients from 10 families with neurodevelopmental disorders, dysmorphic features and intragenic deletions including both exonic (minimal affect all transcripts) and UTR regions.
Majority of variants were inherited, some de novo. But many NMD PTCs in gnomAD (some looking messy, in noncanonical transcript etc.)
Sources: Literature
Mendeliome v1.1332 CASP2 Ain Roesley Marked gene: CASP2 as ready
Mendeliome v1.1332 CASP2 Ain Roesley Gene: casp2 has been classified as Green List (High Evidence).
Mendeliome v1.1332 CASP2 Ain Roesley Classified gene: CASP2 as Green List (high evidence)
Mendeliome v1.1332 CASP2 Ain Roesley Gene: casp2 has been classified as Green List (High Evidence).
Mendeliome v1.1331 CD81 Zornitza Stark Classified gene: CD81 as Green List (high evidence)
Mendeliome v1.1331 CD81 Zornitza Stark Gene: cd81 has been classified as Green List (High Evidence).
Mendeliome v1.1330 LRRC23 Belinda Chong gene: LRRC23 was added
gene: LRRC23 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LRRC23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC23 were set to 37804054
Phenotypes for gene: LRRC23 were set to Non-syndromic male infertility due to sperm motility disorder MONDO:0017173
Review for gene: LRRC23 was set to RED
Added comment: PMID 37804054: A homozygous nonsense mutation in LRRC23 (c.376C>T: p. Arg126X) in an infertile AZS patient whose parents were consanguineous. We verified the adversity of this novel mutation because of its ability to disrupt LRRC23 synthesis and impair RSs integrity. Furthermore, we demonstrated an interaction between LRRC23 and RSPH3 in vitro, indicating that LCCR23 is associated with RS in humans. Meanwhile, the LRRC23-mutant patient had a good prognosis following intracytoplasmic sperm injection.
Sources: Literature
Mendeliome v1.1330 MIEF1 Lucy Spencer gene: MIEF1 was added
gene: MIEF1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MIEF1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MIEF1 were set to 33632269
Phenotypes for gene: MIEF1 were set to Optic atrophy 14 (MIM#620550)
Review for gene: MIEF1 was set to AMBER
Added comment: PMID: 33632269
Inherited optic neuropathies cohort from france with nothing found in OPA1, OPA3 and WFS1 or mtDNA. 2 individuals (55 and 47yo) found to have missense variant in MIEF1, p.Arg146Trp has 35 hets 0 homs in gnomad, p.Tyr240Asn is absent. Both have non-syndromic late onset inherited optic neuropathies characterized by initial loss of peripheral visual fields.

Functional studies in HeLa cells- both missense localised to the mitochondria and formed oligomers similar to WT. MIEF1 normally regulates mitochondrial fission dynamics and causes an increase in mitochondrial fusion events, however both missense variants caused a significantly decreased mitochondrial fusion events.
Sources: Literature
Mendeliome v1.1330 CASP2 Lisa Norbart gene: CASP2 was added
gene: CASP2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CASP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CASP2 were set to 37880421
Phenotypes for gene: CASP2 were set to neurodevelopmental disorder MONDO:0700092, CASP2-related
Penetrance for gene: CASP2 were set to Complete
Review for gene: CASP2 was set to GREEN
gene: CASP2 was marked as current diagnostic
Added comment: 7 patients from 5 families
4 families hom for PTCs, 1 family Chet for splice+PTC
RNA studies done for the splice to indicate usage of two cryptic splice donor sites

5/5 have ID/dev delay
1/5 has seizures
2/5 hypotonia
3/5 lissencephaly (pachygyria and cortical thickening)
Sources: Literature
Mendeliome v1.1330 MAN2B2 Achchuthan Shanmugasundram reviewed gene: MAN2B2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35637269; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1330 CD81 Achchuthan Shanmugasundram reviewed gene: CD81: Rating: GREEN; Mode of pathogenicity: None; Publications: 35849269; Phenotypes: Immunodeficiency, common variable, 6, OMIM:613496; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1330 MME Bryony Thompson Mode of inheritance for gene: MME was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.1329 AXL Zornitza Stark Classified gene: AXL as Red List (low evidence)
Mendeliome v1.1329 AXL Zornitza Stark Gene: axl has been classified as Red List (Low Evidence).
Mendeliome v1.1328 AXL Zornitza Stark reviewed gene: AXL: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.1328 ELANE Zornitza Stark Mode of pathogenicity for gene: ELANE was changed from to Other
Mendeliome v1.1327 ELANE Michelle Torres reviewed gene: ELANE: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 33968054, 3124897; Phenotypes: Neutropaenia, severe congenital 1, autosomal dominant, MIM# 202700, Neutropaenia, cyclic, MIM# 162800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1327 AXIN1 Zornitza Stark changed review comment from: Mouse data only.; to: Caudal duplication: Mouse data only.
Mendeliome v1.1327 AXIN1 Zornitza Stark edited their review of gene: AXIN1: Added comment: PMID: 37582359
- four families (7 individuals) with three homozygous truncating variants.
- all variant shown to result in reduced protein, though 1/3 would be NMD predicted
- Probands had macrocephaly (4/6), GDD (3/7), hip dysplasia (5/6), cardiac anomalies eg. VSD/ASD (3/7), cranial hyperostosis and vertebral endplate sclerosis; Changed rating: GREEN; Changed publications: 37582359; Changed phenotypes: Craniometadiaphyseal osteosclerosis with hip dysplasia, MIM# 620558; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1327 AXIN1 Zornitza Stark Phenotypes for gene: AXIN1 were changed from Caudal duplication anomaly, MIM# 607864; Syndromic disease, (MONDO:0002254), AXIN1-related to Craniometadiaphyseal osteosclerosis with hip dysplasia, MIM# 620558
Mendeliome v1.1326 HMBS Zornitza Stark Mode of inheritance for gene: HMBS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.1325 HMBS Zornitza Stark edited their review of gene: HMBS: Added comment: Rare families with bi-allelic disease reported.; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.1325 SAT1 Chirag Patel Classified gene: SAT1 as Green List (high evidence)
Mendeliome v1.1325 SAT1 Chirag Patel Gene: sat1 has been classified as Green List (High Evidence).
Mendeliome v1.1324 SAT1 Chirag Patel reviewed gene: SAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35977808; Phenotypes: Systemic lupus erythematosus, MONDO:0007915, SAT1-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Mendeliome v1.1324 GPR156 Zornitza Stark Phenotypes for gene: GPR156 were changed from Sensorineural hearing loss, MONDO:60700002, GPR156-related to Deafness, autosomal recessive 121, MIM# 620551
Mendeliome v1.1323 GPR156 Zornitza Stark reviewed gene: GPR156: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal recessive 121, MIM# 620551; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1323 VRK1 Zornitza Stark Phenotypes for gene: VRK1 were changed from Pontocerebellar hypoplasia type 1A, MIM# 607596; Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia to Pontocerebellar hypoplasia type 1A, MIM# 607596; Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia; Neuronopathy, distal hereditary motor, autosomal recessive 10, MIM# 620542
Mendeliome v1.1322 VRK1 Zornitza Stark edited their review of gene: VRK1: Changed phenotypes: Pontocerebellar hypoplasia type 1A, MIM# 607596, Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia, Neuronopathy, distal hereditary motor, autosomal recessive 10, MIM# 620542
Mendeliome v1.1322 HAND2 Zornitza Stark Phenotypes for gene: HAND2 were changed from Congenital heart disease to Congenital heart disease, MONDO:0005453, HAND2-related
Mendeliome v1.1321 KDM5B Zornitza Stark Phenotypes for gene: KDM5B were changed from Mental retardation, autosomal recessive 65 MIM#618109; Intellectual disability and/or autism, autosomal dominant to Mental retardation, autosomal recessive 65 MIM#618109; Neurodevelopmental disorder (MONDO#0700092), KDM5B-related, autosomal dominant
Mendeliome v1.1320 KDM5B Lauren Rogers reviewed gene: KDM5B: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder (MONDO#0700092), KDM5B-related, Intellectual developmental disorder, autosomal recessive 65 (MIM#618109); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1320 PTPN4 Bryony Thompson Publications for gene: PTPN4 were set to 17953619; 25424712; 30238967; DOI: https://doi.org/10.1016/j.xhgg.2021.100033
Mendeliome v1.1319 PTPN4 Bryony Thompson edited their review of gene: PTPN4: Changed publications: 17953619, 25424712, 30238967, 34527963
Mendeliome v1.1319 PTPN4 Bryony Thompson changed review comment from: >3 unrelated probands and supporting mouse model
PMID: 17953619 - knockout mouse model has impaired motor learning and cerebellar synaptic plasticity
PMID: 25424712 - twins with a de novo whole gene deletion and a Rett-like neurodevelopmental disorder
PMID: 30238967 - mosaic de novo variant (p.Leu72Ser) identified in a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems. Also supporting mouse assays demonstrating loss of protein expression in dendritic spines
DOI: https://doi.org/10.1016/j.xhgg.2021.100033 - missense and truncating variants in six unrelated individuals with varying degrees of intellectual disability or developmental delay. 5 were able to undergo segregation analysis and found to be de novo.
Sources: Literature; to: >3 unrelated probands and supporting mouse model
PMID: 17953619 - knockout mouse model has impaired motor learning and cerebellar synaptic plasticity
PMID: 25424712 - twins with a de novo whole gene deletion and a Rett-like neurodevelopmental disorder
PMID: 30238967 - mosaic de novo variant (p.Leu72Ser) identified in a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems. Also supporting mouse assays demonstrating loss of protein expression in dendritic spines
PMID: 34527963 - missense and truncating variants in six unrelated individuals with varying degrees of intellectual disability or developmental delay. 5 were able to undergo segregation analysis and found to be de novo.
Sources: Literature
Mendeliome v1.1319 ZFHX3 Zornitza Stark Deleted their comment
Mendeliome v1.1319 ZFHX3 Zornitza Stark Phenotypes for gene: ZFHX3 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, ZFHX3-related
Mendeliome v1.1318 ZFHX3 Zornitza Stark edited their review of gene: ZFHX3: Added comment: 41 individuals with protein truncating variants (PTVs) or (partial) deletions of ZFHX3. Presentations included (mild) ID and/or behavioural problems, postnatal growth retardation, feeding difficulties, dysmorphism (rarely cleft palate). Nuclear abundance of ZFHX3 increases during human brain development and neuronal differentiation in neural stem cells and SH-SY5Y cells, ZFHX3 interacts with the chromatin remodelling BRG1/Brm-associated factor complex and the cleavage and polyadenylation complex. ZFHX3 haploinsufficiency associates with a specific DNA methylation profile in leukocyte-derived DNA, and participates in chromatin remodelling and mRNA processing.; Changed publications: 37292950; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ZFHX3-related
Mendeliome v1.1318 SMG8 Zornitza Stark Publications for gene: SMG8 were set to PMID: 31130284
Mendeliome v1.1317 EPHA2 Zornitza Stark Publications for gene: EPHA2 were set to 19005574; 19649315; 19306328; 33671840
Mendeliome v1.1316 EPHA2 Zornitza Stark Phenotypes for gene: EPHA2 were changed from cataract 6 multiple types MONDO:0007288 to cataract 6 multiple types MONDO:0007288; microphthalmia, MONDO:0021129, EPHA2-related
Mendeliome v1.1315 EPHA2 Zornitza Stark Mode of inheritance for gene: EPHA2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1314 COG3 Zornitza Stark Phenotypes for gene: COG3 were changed from Neurodevelopmental disorder (MONDO#0700092), COG3-related to Congenital disorder of glycosylation, type IIbb, MIM# 620546
Mendeliome v1.1313 COG3 Zornitza Stark reviewed gene: COG3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type IIbb, MIM# 620546; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1313 ADAMTS15 Zornitza Stark Phenotypes for gene: ADAMTS15 were changed from Arthrogryposis (MONDO:0008779), ADMATS15-related to Arthrogryposis, distal, type 12, MIM# 620545
Mendeliome v1.1312 ADAMTS15 Zornitza Stark reviewed gene: ADAMTS15: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Arthrogryposis, distal, type 12, MIM# 620545; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1312 DNAJB2 Elena Savva Phenotypes for gene: DNAJB2 were changed from Spinal muscular atrophy, distal, autosomal recessive, 5, MIM# 614881; MONDO:0014866 to Neuronopathy, distal hereditary motor, autosomal recessive 5 (MIM#614881)
Mendeliome v1.1311 DNAJB2 Lauren Rogers reviewed gene: DNAJB2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Neuronopathy, distal hereditary motor, autosomal recessive 5 (MIM#614881); Mode of inheritance: None
Mendeliome v1.1311 EGF Zornitza Stark commented on gene: EGF: LIMITED by ClinGen.
Mendeliome v1.1311 EPHA2 Sarah Leigh reviewed gene: EPHA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33671840, 35918037; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1311 SMG8 Sarah Leigh reviewed gene: SMG8: Rating: GREEN; Mode of pathogenicity: None; Publications: 34761517; Phenotypes: ; Mode of inheritance: None
Mendeliome v1.1311 SPTAN1 Zornitza Stark Phenotypes for gene: SPTAN1 were changed from Developmental and epileptic encephalopathy 5, MIM# 613477; Hereditary spastic paraplegia MONDO:0019064, SPTAN1-related; Neuronopathy, distal hereditary motor, 11, autosomal dominant, MIM# 620528 to Developmental and epileptic encephalopathy 5, MIM# 613477; Hereditary spastic paraplegia MONDO:0019064, SPTAN1-related; Neuronopathy, distal hereditary motor, 11, autosomal dominant, MIM# 620528; Autosomal dominant spastic paraplegia-91, with or without cerebellar ataxia (SPG91), MIM#620538
Mendeliome v1.1310 SPTAN1 Zornitza Stark edited their review of gene: SPTAN1: Changed phenotypes: Developmental and epileptic encephalopathy 5, MIM# 613477, Hereditary spastic paraplegia MONDO:0019064, SPTAN1-related, Neuronopathy, distal hereditary motor, 11, autosomal dominant, MIM# 620528, Autosomal dominant spastic paraplegia-91, with or without cerebellar ataxia (SPG91), MIM#620538
Mendeliome v1.1310 COQ7 Zornitza Stark Phenotypes for gene: COQ7 were changed from Coenzyme Q10 deficiency, primary, 8 MIM#616733 to Coenzyme Q10 deficiency, primary, 8 MIM#616733; Neuronopathy, distal hereditary motor, autosomal recessive 9, MIM# 620402
Mendeliome v1.1309 COQ7 Zornitza Stark Publications for gene: COQ7 were set to 26084283; 31240163; 33215859; 28409910
Mendeliome v1.1308 COQ7 Zornitza Stark reviewed gene: COQ7: Rating: GREEN; Mode of pathogenicity: None; Publications: 36758993, 36759155; Phenotypes: Neuronopathy, distal hereditary motor, autosomal recessive 9, MIM# 620402; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1308 ZFHX3 Chirag Patel Classified gene: ZFHX3 as Green List (high evidence)
Mendeliome v1.1308 ZFHX3 Chirag Patel Gene: zfhx3 has been classified as Green List (High Evidence).
Mendeliome v1.1307 ZFHX3 Chirag Patel Classified gene: ZFHX3 as Green List (high evidence)
Mendeliome v1.1307 ZFHX3 Chirag Patel Gene: zfhx3 has been classified as Green List (High Evidence).
Mendeliome v1.1306 ZFHX3 Chirag Patel reviewed gene: ZFHX3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37292950; Phenotypes: Neurodevelopmental disorder; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1306 KDM2B Ain Roesley edited their review of gene: KDM2B: Changed phenotypes: neurodevelopmental disorder MONDO#0700092, KDM2B-related
Mendeliome v1.1306 KDM2B Ain Roesley Phenotypes for gene: KDM2B were changed from neurodevelopmental disorder MONDO#070009, KDM2B-related to neurodevelopmental disorder MONDO#0700092, KDM2B-related
Mendeliome v1.1305 FAM83G Zornitza Stark Phenotypes for gene: FAM83G were changed from Palmoplantar keratoderma, curly scalp hair and toenail dystrophy to Hereditary palmoplantar keratoderma, MONDO:0019272, FAM83G-related
Mendeliome v1.1304 FAM83G Zornitza Stark edited their review of gene: FAM83G: Changed phenotypes: Hereditary palmoplantar keratoderma, MONDO:0019272, FAM83G-related
Mendeliome v1.1304 FAAP24 Zornitza Stark Phenotypes for gene: FAAP24 were changed from EBV infection-driven lymphoproliferative disease to Immunodeficiency-associated lymphoproliferative disease, MONDO:0020083, FAAP24-related
Mendeliome v1.1303 FAAP24 Zornitza Stark edited their review of gene: FAAP24: Changed phenotypes: Immunodeficiency-associated lymphoproliferative disease, MONDO:0020083, FAAP24-related
Mendeliome v1.1303 IL23R Zornitza Stark Phenotypes for gene: IL23R were changed from Immunodeficiency disease, MONDO:0021094; Susceptibility to mycobacteria and Salmonella to Immunodeficiency disease, MONDO:0021094; Inherited susceptibility to mycobacterial disease, MONDO:0019146, IL23R-related
Mendeliome v1.1302 IL23R Zornitza Stark Publications for gene: IL23R were set to 30578351; 35829840
Mendeliome v1.1301 IL23R Zornitza Stark Classified gene: IL23R as Green List (high evidence)
Mendeliome v1.1301 IL23R Zornitza Stark Gene: il23r has been classified as Green List (High Evidence).
Mendeliome v1.1300 IL23R Zornitza Stark edited their review of gene: IL23R: Added comment: PMID 36763636: Six individuals from four unrelated Iranian kindreds with AR complete IL-23R deficiency presenting MSMD with complete penetrance. Also some patients with susceptibility to CMC with incomplete penetrance.; Changed rating: GREEN; Changed publications: 30578351, 35829840, 36763636; Changed phenotypes: Immunodeficiency disease, MONDO:0021094, Inherited susceptibility to mycobacterial disease, MONDO:0019146, IL23R-related
Mendeliome v1.1300 IRF1 Zornitza Stark Phenotypes for gene: IRF1 were changed from to Inherited susceptibility to mycobacterial disease, MONDO:0019146, IRF1-related
Mendeliome v1.1299 IRF1 Zornitza Stark Publications for gene: IRF1 were set to
Mendeliome v1.1298 IRF1 Zornitza Stark Mode of inheritance for gene: IRF1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1297 IRF1 Zornitza Stark Classified gene: IRF1 as Green List (high evidence)
Mendeliome v1.1297 IRF1 Zornitza Stark Gene: irf1 has been classified as Green List (High Evidence).
Mendeliome v1.1296 IRF1 Zornitza Stark edited their review of gene: IRF1: Added comment: PMID 36736301: Two unrelated children with recurrent early-onset life-threatening mycobacterial diseases due to multiple mycobacteria (BCG, M. avium). Homozygous LoF vairiants with extensive supporting functional data.; Changed rating: GREEN; Changed publications: 36736301; Changed phenotypes: Inherited susceptibility to mycobacterial disease, MONDO:0019146, IRF1-related; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1296 IRF4 Zornitza Stark Phenotypes for gene: IRF4 were changed from Whipple's disease; [Skin/hair/eye pigmentation, variation in, 8] 611724; Combined immunodeficiency to Combined immunodeficiency, MONDO:0015131, IRF4-related
Mendeliome v1.1295 IRF4 Zornitza Stark Publications for gene: IRF4 were set to 29537367; 29408330
Mendeliome v1.1294 IRF4 Zornitza Stark Classified gene: IRF4 as Green List (high evidence)
Mendeliome v1.1294 IRF4 Zornitza Stark Gene: irf4 has been classified as Green List (High Evidence).
Mendeliome v1.1293 IRF4 Zornitza Stark edited their review of gene: IRF4: Added comment: PMID 36662884: Seven individuals with profound CID from six kindreds of diverse ethnic origins (Fig. 1A). All affected individuals suffered with early onset (<1 year of age) recurrent sinopulmonary infections, with the opportunistic pathogen Pneumocystis jirovecii causing pneumonia in most individuals. p.T95R variant found in all patients. Extensive functional data including knockout mouse model. The heterozygous IRF4T95R variant found in multiple unrelated families caused a fully penetrant, severe very early-onset immunodeficiency characterized by greatly enhanced susceptibility to opportunistic pathogens such as P. jirovecii and weakly pathogenic mycobacteria.; Changed rating: GREEN; Changed publications: 29537367, 36662884; Changed phenotypes: Combined immunodeficiency, MONDO:0015131, IRF4-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1293 MCM9 Zornitza Stark Publications for gene: MCM9 were set to 25480036; 26771056; 33538981; 33095795
Mendeliome v1.1292 MCM9 Zornitza Stark Phenotypes for gene: MCM9 were changed from Ovarian dysgenesis 4, MIM# 616185 to Ovarian dysgenesis 4, MIM# 616185; Hereditary neoplastic syndrome MONDO:0015356
Mendeliome v1.1291 CR2 Zornitza Stark Publications for gene: CR2 were set to 22035880; 26325596
Mendeliome v1.1290 CR2 Zornitza Stark Classified gene: CR2 as Green List (high evidence)
Mendeliome v1.1290 CR2 Zornitza Stark Gene: cr2 has been classified as Green List (High Evidence).
Mendeliome v1.1289 CR2 Zornitza Stark edited their review of gene: CR2: Added comment: PMID:28499783 reported two siblings from consanguineous parents, both with a homozygous frameshift variant in CR2 and with recurrent respiratory infections and hypogammaglobulinaemia.; Changed rating: GREEN; Changed publications: 22035880, 26325596, 28499783
Mendeliome v1.1289 HMOX1 Zornitza Stark Publications for gene: HMOX1 were set to 21088618; 9884342; 20844238
Mendeliome v1.1288 HMOX1 Zornitza Stark Classified gene: HMOX1 as Green List (high evidence)
Mendeliome v1.1288 HMOX1 Zornitza Stark Gene: hmox1 has been classified as Green List (High Evidence).
Mendeliome v1.1287 HMOX1 Zornitza Stark edited their review of gene: HMOX1: Added comment: PMID:33066778 provides a third case in support of promoting HMOX1 to green rating. This third case is a boy born to nonconsanguineous parents who presented with early onset asplenia, recurrent infections, and associated flares with bone marrow histiocyte activation with worsening interstitial lung disease and joint pain. This boy harboured compound heterozygous variants (p.L89Sfs*24 and p.Ala88Profs*51).; Changed rating: GREEN; Changed publications: 21088618, 9884342, 20844238, 33066778
Mendeliome v1.1287 HYOU1 Zornitza Stark Classified gene: HYOU1 as Green List (high evidence)
Mendeliome v1.1287 HYOU1 Zornitza Stark Gene: hyou1 has been classified as Green List (High Evidence).
Mendeliome v1.1286 HYOU1 Zornitza Stark changed review comment from: PMID:35549617 reported another case with homozgyous variant (p.Arg486Cys) and anemia, thrombocytopenia and severe panleukopenia and immunodeficiency.; to: PMID:35549617 reported another case with homozgyous variant (p.Arg486Cys) and anaemia, thrombocytopenia and severe panleukopenia and immunodeficiency.
Mendeliome v1.1286 HYOU1 Zornitza Stark edited their review of gene: HYOU1: Added comment: PMID:35549617 reported another case with homozgyous variant (p.Arg486Cys) and anemia, thrombocytopenia and severe panleukopenia and immunodeficiency.; Changed rating: GREEN; Changed publications: 27913302, 35822684, 35549617
Mendeliome v1.1286 KCNH5 Zornitza Stark edited their review of gene: KCNH5: Changed phenotypes: Developmental and epileptic encephalopathy 112, MIM# 620537
Mendeliome v1.1286 KCNH5 Zornitza Stark reviewed gene: KCNH5: Rating: GREEN; Mode of pathogenicity: None; Publications: 36307226; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1286 KCNH5 Zornitza Stark Phenotypes for gene: KCNH5 were changed from Neurodevelopmental disorder MONDO#0700092, KCNH5-related to Developmental and epileptic encephalopathy 112, MIM# 620537
Mendeliome v1.1285 ERLIN2 Zornitza Stark Phenotypes for gene: ERLIN2 were changed from hereditary spastic paraplegia 18 MONDO:0012639; Spastic paraplegia 18A, autosomal dominant, MIM# 620512 to Spastic paraplegia 18, autosomal recessive, MIM# 611225; Spastic paraplegia 18A, autosomal dominant, MIM# 620512
Mendeliome v1.1284 ERLIN2 Zornitza Stark edited their review of gene: ERLIN2: Changed phenotypes: Spastic paraplegia 18, autosomal recessive, MIM# 611225, Spastic paraplegia 18A, autosomal dominant, MIM# 620512; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1284 ERLIN2 Zornitza Stark Phenotypes for gene: ERLIN2 were changed from hereditary spastic paraplegia 18 MONDO:0012639 to hereditary spastic paraplegia 18 MONDO:0012639; Spastic paraplegia 18A, autosomal dominant, MIM# 620512
Mendeliome v1.1283 ERLIN2 Zornitza Stark reviewed gene: ERLIN2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 18A, autosomal dominant, MIM# 620512; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1283 MCM9 Natalie Tan changed review comment from: Emerging association in individuals with biallelic variants of a combined phenotype of primary ovarian insufficiency and a Lynch-like syndrome/early-onset colorectal cancer (PMID: 26806154, 34556653). Monoallelic carriers have also been reported with a Lynch-like syndrome (32841224). Association of primary ovarian insufficiency with other malignancies is less clear (32613604, 34556653). See PMID 37378315 for review of literature to April 2023.; to: Emerging association in individuals with biallelic variants of a combined phenotype of primary ovarian insufficiency and a Lynch-like syndrome/early-onset colorectal cancer (PMID: 26806154, 34556653). Monoallelic carriers have also been reported with a Lynch-like syndrome (32841224). Association of primary ovarian insufficiency with other malignancies is less clear (32613604, 34556653). See PMID 37378315 for review of literature to April 2023.
Mendeliome v1.1283 MCM9 Natalie Tan reviewed gene: MCM9: Rating: GREEN; Mode of pathogenicity: None; Publications: (PMID: 26806154, 34556653, 32841224, 32613604, 37378315); Phenotypes: Primary ovarian insufficiency, Lynch-like syndrome/colorectal cancer; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1283 U2AF2 Zornitza Stark Phenotypes for gene: U2AF2 were changed from Neurodevelopmental disorder MONDO:0700092, U2AF2-related to Developmental delay, dysmorphic facies, and brain anomalies, MIM# 620535
Mendeliome v1.1282 EYA3 Zornitza Stark Phenotypes for gene: EYA3 were changed from Oculo-auriculo-vertebral spectrum (OAVS) to Oculo-auriculo-vertebral spectrum (OAVS), MONDO:0015397, EYA3-related
Mendeliome v1.1281 ETS1 Zornitza Stark Phenotypes for gene: ETS1 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, ETS1-related
Mendeliome v1.1280 ETS1 Zornitza Stark edited their review of gene: ETS1: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ETS1-related
Mendeliome v1.1280 ERBIN Zornitza Stark Phenotypes for gene: ERBIN were changed from Recurrent respiratory infections; Susceptibility to S.aureus; Eczema; Hyperextensible joints; Scoliosis; Arterial dilatation in some to Combined immunodeficiency, MONDO:0015131, ERBIN-related; Recurrent respiratory infections; Susceptibility to S.aureus; Eczema; Hyperextensible joints; Scoliosis; Arterial dilatation in some
Mendeliome v1.1279 ERBIN Zornitza Stark edited their review of gene: ERBIN: Changed phenotypes: Combined immunodeficiency, MONDO:0015131, ERBIN-related, Recurrent respiratory infections, Susceptibility to S.aureus, Eczema, Hyperextensible joints, Scoliosis, Arterial dilatation in some
Mendeliome v1.1279 EPHX1 Zornitza Stark Phenotypes for gene: EPHX1 were changed from Lipoatrophic diabetes to Hereditary lipodystrophy, MONDO:0020087, EPHX1-related
Mendeliome v1.1278 EPHX1 Zornitza Stark edited their review of gene: EPHX1: Changed phenotypes: Hereditary lipodystrophy, MONDO:0020087, EPHX1-related
Mendeliome v1.1278 EPHA7 Zornitza Stark Phenotypes for gene: EPHA7 were changed from Intellectual disability to Neurodevelopmental disorder MONDO:0700092,EPHA7-related
Mendeliome v1.1277 EPHA7 Zornitza Stark edited their review of gene: EPHA7: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092,EPHA7-related
Mendeliome v1.1277 EOMES Zornitza Stark Phenotypes for gene: EOMES were changed from Microcephaly to Microcephaly, MONDO:0001149, EOMES-related
Mendeliome v1.1276 EOMES Zornitza Stark edited their review of gene: EOMES: Changed phenotypes: Microcephaly, MONDO:0001149, EOMES-related
Mendeliome v1.1276 ENO1 Zornitza Stark Phenotypes for gene: ENO1 were changed from Polymicrogyria to Polymicrogyria, MONDO:0000087, ENO1-related
Mendeliome v1.1275 ELMOD1 Zornitza Stark Phenotypes for gene: ELMOD1 were changed from Intellectual disability to Neurodevelopmental disorder MONDO:0700092,ELMOD1-related
Mendeliome v1.1274 ELMOD1 Zornitza Stark edited their review of gene: ELMOD1: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092,ELMOD1-related
Mendeliome v1.1274 EIF4ENIF1 Zornitza Stark Phenotypes for gene: EIF4ENIF1 were changed from Primary ovarian insufficiency to Primary ovarian insufficiency, MONDO:0005387, EIF4ENIF1-related
Mendeliome v1.1273 EHBP1L1 Zornitza Stark Phenotypes for gene: EHBP1L1 were changed from Non-immune hydrops fetalis to Non-immune hydrops fetalis, MONDO:0015193, EHBP1l1-related
Mendeliome v1.1272 EEF1D Zornitza Stark Phenotypes for gene: EEF1D were changed from Intellectual disability to Neurodevelopmental disorder MONDO:0700092, EEF1D-related
Mendeliome v1.1271 EEF1D Zornitza Stark edited their review of gene: EEF1D: Changed phenotypes: Neurodevelopmental disorder MONDO:0700092, EEF1D-related
Mendeliome v1.1271 DYNC1I1 Zornitza Stark Phenotypes for gene: DYNC1I1 were changed from Split-hand/split-foot malformation (SHFM) to Split-hand/split-foot malformation (SHFM) MONDO:0016576, DYNC1I1-related
Mendeliome v1.1270 DSCR3 Zornitza Stark Phenotypes for gene: DSCR3 were changed from Intellectual disability, no OMIM # yet to Neurodevelopmental disorder (MONDO:0700092), DSCR3-related
Mendeliome v1.1269 DSCR3 Zornitza Stark edited their review of gene: DSCR3: Changed phenotypes: Neurodevelopmental disorder (MONDO:0700092), DSCR3-related
Mendeliome v1.1269 STAT6 Zornitza Stark Phenotypes for gene: STAT6 were changed from Allergic disease, MONDO:0005271, STAT6-related; early-onset multiorgan allergies to Hyper-IgE syndrome 6, autosomal dominant, with atopy and allergies, MIM# 620532
Mendeliome v1.1268 STAT6 Zornitza Stark edited their review of gene: STAT6: Changed phenotypes: Hyper-IgE syndrome 6, autosomal dominant, with atopy and allergies, MIM# 620532
Mendeliome v1.1268 SRP68 Zornitza Stark Marked gene: SRP68 as ready
Mendeliome v1.1268 SRP68 Zornitza Stark Gene: srp68 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1268 SRP68 Zornitza Stark Classified gene: SRP68 as Amber List (moderate evidence)
Mendeliome v1.1268 SRP68 Zornitza Stark Gene: srp68 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1267 SRP68 Zornitza Stark gene: SRP68 was added
gene: SRP68 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SRP68 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SRP68 were set to 32273475
Phenotypes for gene: SRP68 were set to Neutropenia, severe congenital, 10, autosomal recessive, MIM# 620534
Review for gene: SRP68 was set to AMBER
Added comment: Single individual reported with bi-allelic LoF variants and presenting with infantile-onset severe neutropenia and recurrent infections. Multiple lines of functional evidence provided.
Sources: Expert list
Mendeliome v1.1266 PLS3 Zornitza Stark Phenotypes for gene: PLS3 were changed from Bone mineral density QTL18, osteoporosis - MIM#300910 to Bone mineral density QTL18, osteoporosis - MIM#300910; congenital diaphragmatic hernia MONDO:0005711, PLS3-related
Mendeliome v1.1265 PLS3 Zornitza Stark Publications for gene: PLS3 were set to 32655496; 25209159; 29736964; 29884797; 28777485; 24088043
Mendeliome v1.1264 PLS3 Zornitza Stark Mode of inheritance for gene: PLS3 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.1263 PLS3 Zornitza Stark edited their review of gene: PLS3: Added comment: PMID 37751738: 8 unrelated families with affected males with an X-linked condition characterised by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. All were missense variants. A mouse knock in model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Gain-of-function is a suggested mechanism.; Changed publications: 32655496, 25209159, 29736964, 29884797, 28777485, 24088043, 37751738; Changed phenotypes: Bone mineral density QTL18, osteoporosis - MIM#300910, congenital diaphragmatic hernia MONDO:0005711, PLS3-related; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.1263 EFCAB7 Zornitza Stark Marked gene: EFCAB7 as ready
Mendeliome v1.1263 EFCAB7 Zornitza Stark Gene: efcab7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1263 EFCAB7 Zornitza Stark Classified gene: EFCAB7 as Amber List (moderate evidence)
Mendeliome v1.1263 EFCAB7 Zornitza Stark Gene: efcab7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1262 MYCN Elena Savva Phenotypes for gene: MYCN were changed from Feingold syndrome 1; megalencephaly; ventriculomegaly; hypoplastic corpus callosum; intellectual disability; polydactyly; neuroblastoma to Neurodevelopmental disorder (MONDO:0700092), MYCN-related; Feingold syndrome 1 MIM#164280
Mendeliome v1.1261 CDC23 Zornitza Stark Marked gene: CDC23 as ready
Mendeliome v1.1261 CDC23 Zornitza Stark Gene: cdc23 has been classified as Green List (High Evidence).
Mendeliome v1.1261 MYCN Elena Savva Publications for gene: MYCN were set to 21224895; 8470948; 30573562
Mendeliome v1.1260 CDC23 Zornitza Stark Classified gene: CDC23 as Green List (high evidence)
Mendeliome v1.1260 CDC23 Zornitza Stark Gene: cdc23 has been classified as Green List (High Evidence).
Mendeliome v1.1259 CFAP20 Ain Roesley Marked gene: CFAP20 as ready
Mendeliome v1.1259 CFAP20 Ain Roesley Gene: cfap20 has been classified as Green List (High Evidence).
Mendeliome v1.1259 CFAP20 Ain Roesley Phenotypes for gene: CFAP20 were changed from Retinitis pigmentosa (MONDO:0019200) to Retinitis pigmentosa (MONDO:0019200), CFAP20-related
Mendeliome v1.1258 CFAP20 Ain Roesley Classified gene: CFAP20 as Green List (high evidence)
Mendeliome v1.1258 CFAP20 Ain Roesley Gene: cfap20 has been classified as Green List (High Evidence).
Mendeliome v1.1257 COG3 Elena Savva Classified gene: COG3 as Amber List (moderate evidence)
Mendeliome v1.1257 COG3 Elena Savva Gene: cog3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1256 COG3 Elena Savva Classified gene: COG3 as Amber List (moderate evidence)
Mendeliome v1.1256 COG3 Elena Savva Gene: cog3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1255 COG3 Elena Savva Marked gene: COG3 as ready
Mendeliome v1.1255 COG3 Elena Savva Gene: cog3 has been removed from the panel.
Mendeliome v1.1255 EFCAB7 Melanie Marty gene: EFCAB7 was added
gene: EFCAB7 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EFCAB7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFCAB7 were set to PMID: 37684519
Phenotypes for gene: EFCAB7 were set to Polydactyly (MONDO:0021003), EFCAB7-related
Review for gene: EFCAB7 was set to AMBER
Added comment: PMID: 37684519: two homozygous frameshift variants were identified by exome sequencing in four consanguinous Pakistani families, 3 families with p.(Gly277Valfs*5) and 1 family with p.(Asn451Phefs*2). Variants segregated with disease and het carriers were unaffected. Counting as 2 families to be conservative.
Sources: Literature
Mendeliome v1.1254 CFAP20 Sarah Pantaleo gene: CFAP20 was added
gene: CFAP20 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CFAP20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP20 were set to PMID:36329026
Phenotypes for gene: CFAP20 were set to Retinitis pigmentosa (MONDO:0019200)
Review for gene: CFAP20 was set to GREEN
Added comment: CFAP20 is a ciliopathy candidate. Demonstrate in zebrafish that cfap20 is required for motile cilia function, and in C. elegans, CFAP-20 maintains the structural integrity of non-motile cilia inner junctions, influencing sensory-dependent signalling and development.

Human patients and zebrafish with CFAP20 mutations both exhibit retinal dystrophy (retinitis pigments). Hence, CFAP20 functions within a structural./functional hub centred on the inner junction that is shared between motile and non-motile cilia, and is distinct from other ciliopathy-associaetd domains or macromolecular complexes.

Describe 8 individuals from 4 independent families with damaging biallelic variants (homozygous or compound heterozygous) in CFAP20 that segregate with retinal dystrophy. All variants cluster to one side of the protein, with two of the residues directly contacting alpha-tubullin.

Family 1 - consanguineous set of 3 siblings from Sudan, homozygous for CFAP20 c.305G>A; p.Arg102His (they also had a homozygous variant in DYNC1LI2 however CFAP20 was considered the better candidate.
Family 2 - 3 siblings from Spain, 2 with retinal dystrophy, 1 genetically tested and has c.337C>T; p.(Arg113Trp) and c.397delC; p.(Gln133Serfs*5)
Family 3 - single affected family member compound het for c.164+1G>A and c.457A>G; p.(Arg153Gly).
Family 4 - 3 affected siblings with generalised retinopathy and variable neurological deficits with c.164+1G>A and c.257G>A; p.(Tyr86Cys)

For all families, no individuals had signs of polycystic kidney disease; however, not all individuals had kidney imaging. Visual defecit phenotype presented between adolescence and adulthood (17-56 years old).

Used HEK293T cell expression studies to demonstrate a statistically significant decline of mutated CFAP20 protein levels (with the exception of p.Arg102His). To test the specific variants, they used the C.elegans orthologues.
Sources: Literature
Mendeliome v1.1255 GPRASP1 Elena Savva Classified gene: GPRASP1 as Amber List (moderate evidence)
Mendeliome v1.1255 GPRASP1 Elena Savva Gene: gprasp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1254 GPRASP1 Elena Savva Classified gene: GPRASP1 as Amber List (moderate evidence)
Mendeliome v1.1254 GPRASP1 Elena Savva Gene: gprasp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1253 GPRASP1 Elena Savva Classified gene: GPRASP1 as Amber List (moderate evidence)
Mendeliome v1.1253 GPRASP1 Elena Savva Gene: gprasp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1252 GPRASP1 Elena Savva Marked gene: GPRASP1 as ready
Mendeliome v1.1252 GPRASP1 Elena Savva Gene: gprasp1 has been removed from the panel.
Mendeliome v1.1252 MYCN Naomi Baker reviewed gene: MYCN: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID:37710961; Phenotypes: Neurodevelopmental disorder (MONDO:0700092), MYCN-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1252 MAST4 Ain Roesley Marked gene: MAST4 as ready
Mendeliome v1.1252 MAST4 Ain Roesley Gene: mast4 has been classified as Green List (High Evidence).
Mendeliome v1.1252 MAST4 Ain Roesley Classified gene: MAST4 as Green List (high evidence)
Mendeliome v1.1252 MAST4 Ain Roesley Gene: mast4 has been classified as Green List (High Evidence).
Mendeliome v1.1251 CDC23 Michelle Torres gene: CDC23 was added
gene: CDC23 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CDC23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDC23 were set to 37768355
Phenotypes for gene: CDC23 were set to inherited oocyte maturation defect MONDO#0014769, CDC23-related
Review for gene: CDC23 was set to GREEN
Added comment: Two missense variants, p.(Y329C) and p.(R330C), detected in three unrelated homozygous infertile females characterised by oocyte maturation defects.

In vitro studies using HeLa cells showed either decreased protein levels (Y329C) or impaired localisation (R330C). In vivo studies in mice homozygous for Y329C reproduced patient’s phenotype.
Sources: Literature
Mendeliome v1.1251 GPRASP1 Paul De Fazio gene: GPRASP1 was added
gene: GPRASP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GPRASP1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: GPRASP1 were set to 37787182
Phenotypes for gene: GPRASP1 were set to Arteriovenous hemangioma/malformation, GPRASP1-related, MONDO:0001256
Penetrance for gene: GPRASP1 were set to unknown
Review for gene: GPRASP1 was set to AMBER
gene: GPRASP1 was marked as current diagnostic
Added comment: Two hemizygous germline missense variants, p.Arg1167Trp and p.Trp553Cys, were identified in three male patients presenting with spinal AVM, Cobb syndrome, or scalp AVM. The variants were inherited from unaffected heterozygous mothers. Note that p.Arg1167Trp has hemizygous (>70) and homozygous individuals reported in gnomAD.

The variants were found to result in LoF in endothelial cells. Endothelial Gprasp1 knockout mice suffered a high probability of cerebral hemorrhage, AVMs, and exhibited vascular anomalies in multiple organs.
Sources: Literature
Mendeliome v1.1251 COG3 Daniel Flanagan gene: COG3 was added
gene: COG3 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: COG3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COG3 were set to PMID: 37711075
Phenotypes for gene: COG3 were set to Neurodevelopmental disorder (MONDO#0700092), COG3-related
Review for gene: COG3 was set to AMBER
Added comment: Two COG3 homozygous missense variants in four individuals from two unrelated consanguineous families. Clinical phenotypes of affected individuals include global developmental delay, severe intellectual disability, microcephaly, epilepsy, facial dysmorphism, and variable neurological findings.
Sources: Expert list
Mendeliome v1.1251 ATP2B2 Zornitza Stark Phenotypes for gene: ATP2B2 were changed from Deafness, autosomal dominant 82, MIM# 619804; {Deafness, autosomal recessive 12, modifier of}, MIM# 601386 to Deafness, autosomal dominant 82, MIM# 619804; Neurodevelopmental Disorder, MONDO:0700092, ATP2B2-related
Mendeliome v1.1250 ATP2B2 Zornitza Stark Publications for gene: ATP2B2 were set to 30535804; 15829536
Mendeliome v1.1249 MAST4 Ain Roesley gene: MAST4 was added
gene: MAST4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MAST4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAST4 were set to 36910266; 33057194
Phenotypes for gene: MAST4 were set to neurodevelopmental disorder MONDO:0700092, MAST4-related
Penetrance for gene: MAST4 were set to Complete
Review for gene: MAST4 was set to GREEN
gene: MAST4 was marked as current diagnostic
Added comment: PMID: 36910266 - 4 families with 4 affecteds, all de novo missense

2x borderline microcephaly (-2SD)
2x gross motor delay
2x dysmorphism
4x ID + seizures
3x abnormal brain MRI findings

PMID: 33057194 - 5x de novos, 4x missense + 1x PTC
Cohort of individuals with severe developmental disorder
individual phenotypic information not provided


Recurrent variants are Thr1471Ile (3x) and Ser1181Phe)
Sources: Literature
Mendeliome v1.1248 ZBTB47 Elena Savva Marked gene: ZBTB47 as ready
Mendeliome v1.1248 ZBTB47 Elena Savva Gene: zbtb47 has been classified as Green List (High Evidence).
Mendeliome v1.1248 ZBTB47 Elena Savva Classified gene: ZBTB47 as Green List (high evidence)
Mendeliome v1.1248 ZBTB47 Elena Savva Gene: zbtb47 has been classified as Green List (High Evidence).
Mendeliome v1.1247 ZBTB47 Elena Savva gene: ZBTB47 was added
gene: ZBTB47 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZBTB47 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZBTB47 were set to 37743782
Phenotypes for gene: ZBTB47 were set to Neurodevelopmental disorder (MONDO#0700092), ZBTB47-related
Review for gene: ZBTB47 was set to GREEN
Added comment: PMID 37743782:
- 5 patients with de novo missense, 4/5 have a recurring p.Gly477Lys. Probands have intellectual disability (5/5), seizures (5/5), hypotonia (5/5), gait abnormalities, and variable movement abnormalities (5/5).
- Missense variants are positioned close to His and Cys residues involved in forming C2H2 zinc fingers.
- No functional studies performed
- Minimal PTCs in gnomAD
Sources: Literature
Mendeliome v1.1246 KIF4A Zornitza Stark Phenotypes for gene: KIF4A were changed from Mental retardation, X-linked 100, MIM# 300923 to Mental retardation, X-linked 100, MIM# 300923; Taurodontism, microdontia, and dens invaginatus (MIM#313490)
Mendeliome v1.1245 ATP2B2 Andrew Fennell reviewed gene: ATP2B2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 37675773; Phenotypes: Neurodevelopmental Disorder, MONDO:0700092, ATP2B2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1245 KIF4A Lucy Spencer reviewed gene: KIF4A: Rating: AMBER; Mode of pathogenicity: None; Publications: 31616463; Phenotypes: Taurodontism, microdontia, and dens invaginatus (MIM#313490); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.1245 ATRX Zornitza Stark Phenotypes for gene: ATRX were changed from Alpha-thalassemia/mental retardation syndrome, MIM# 301040; Intellectual disability-hypotonic facies syndrome, X-linked, MIM# 309580 to ATR-X-related syndrome MONDO:0016980
Mendeliome v1.1244 DLG5 Zornitza Stark Phenotypes for gene: DLG5 were changed from Cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations to Ciliopathy, MONDO:0016044, DLG5-related; Cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations
Mendeliome v1.1243 DHX32 Zornitza Stark Phenotypes for gene: DHX32 were changed from Intellectual disability, spastic diplegia, dystonia, brain abnormalities to Neurodevelopmental disorder, MONDO:0700092, DHX32-related
Mendeliome v1.1242 DGAT2 Zornitza Stark Phenotypes for gene: DGAT2 were changed from axonal Charcot-Marie-Tooth disease to Charcot-Marie-Tooth disease, MONDO:0015626, DGAT2-related
Mendeliome v1.1241 DDX54 Zornitza Stark Phenotypes for gene: DDX54 were changed from Intellectual disability; congenital anomalies to Neurodevelopmental disorder, MONDO:0700092, DDX54-related
Mendeliome v1.1240 DDX54 Zornitza Stark edited their review of gene: DDX54: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, DDX54-related
Mendeliome v1.1240 DDX23 Zornitza Stark Phenotypes for gene: DDX23 were changed from DDX23-associated neurodevelopmental disorder to Neurodevelopmental disorder, MONDO:0700092, DDX23-related
Mendeliome v1.1239 DDX23 Zornitza Stark edited their review of gene: DDX23: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, DDX23-related
Mendeliome v1.1239 CSNK1G1 Zornitza Stark Phenotypes for gene: CSNK1G1 were changed from Global developmental delay; Intellectual disability; Autism; Seizures to Neurodevelopmental disorder, MONDO:0700092, CSNK1G-related
Mendeliome v1.1238 CSNK1G1 Zornitza Stark edited their review of gene: CSNK1G1: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, CSNK1G-related
Mendeliome v1.1238 SPTAN1 Zornitza Stark Phenotypes for gene: SPTAN1 were changed from Developmental and epileptic encephalopathy 5, MIM# 613477; Hereditary spastic paraplegia MONDO:0019064, SPTAN1-related; hereditary motor neuropathy to Developmental and epileptic encephalopathy 5, MIM# 613477; Hereditary spastic paraplegia MONDO:0019064, SPTAN1-related; Neuronopathy, distal hereditary motor, 11, autosomal dominant, MIM# 620528
Mendeliome v1.1237 SPTAN1 Zornitza Stark edited their review of gene: SPTAN1: Changed phenotypes: Developmental and epileptic encephalopathy 5, MIM# 613477, Hereditary spastic paraplegia MONDO:0019064, SPTAN1-related, Neuronopathy, distal hereditary motor, 11, autosomal dominant, MIM# 620528
Mendeliome v1.1237 DAZL Zornitza Stark Phenotypes for gene: DAZL were changed from Primary ovarian insufficiency to Primary ovarian failure, MONDO:0005387, DAZL-related
Mendeliome v1.1236 DACH2 Zornitza Stark Phenotypes for gene: DACH2 were changed from Primary ovarian insufficiency to Primary ovarian failure, MONDO:0005387, DACH2-related
Mendeliome v1.1235 CYBRD1 Zornitza Stark Phenotypes for gene: CYBRD1 were changed from Iron overload to Iron metabolism disease, MONDO:0002279, CYBRD1-related
Mendeliome v1.1234 CYBRD1 Zornitza Stark edited their review of gene: CYBRD1: Changed phenotypes: Iron metabolism disease, MONDO:0002279, CYBRD1-related
Mendeliome v1.1234 CTNND2 Zornitza Stark Phenotypes for gene: CTNND2 were changed from Intellectual disability; Autism; Epilepsy to Neurodevelopmental disorder, MONDO:0700092, CTNND2-related
Mendeliome v1.1233 CTNNBL1 Zornitza Stark Phenotypes for gene: CTNNBL1 were changed from Primary Immunodeficiency; Autoimmune Cytopenias; Common variable immunodeficiency to Immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, MIM# 619846
Mendeliome v1.1232 CTNNBL1 Zornitza Stark edited their review of gene: CTNNBL1: Changed phenotypes: Immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, MIM# 619846
Mendeliome v1.1232 CSNK1E Zornitza Stark Phenotypes for gene: CSNK1E were changed from Epileptic encephalopathy to Developmental and epileptic encephalopathy, MONDO:0100062, CSNK1E-related
Mendeliome v1.1231 CSGALNACT1 Zornitza Stark Phenotypes for gene: CSGALNACT1 were changed from Congenital disorders of glycosylation; skeletal dysplasia; advanced bone age to Skeletal dysplasia, mild, with joint laxity and advanced bone age, MIM# 618870
Mendeliome v1.1230 CSGALNACT1 Zornitza Stark edited their review of gene: CSGALNACT1: Changed phenotypes: Skeletal dysplasia, mild, with joint laxity and advanced bone age, MIM# 618870
Mendeliome v1.1230 CSDE1 Zornitza Stark Phenotypes for gene: CSDE1 were changed from Autism; intellectual disability; seizures; macrocephaly to Neurodevelopmental disorder, MONDO:0700092, CSDE1-related
Mendeliome v1.1229 CSDE1 Zornitza Stark edited their review of gene: CSDE1: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, CSDE1-related
Mendeliome v1.1229 CASP4 Zornitza Stark Marked gene: CASP4 as ready
Mendeliome v1.1229 CASP4 Zornitza Stark Gene: casp4 has been classified as Red List (Low Evidence).
Mendeliome v1.1229 CASP4 Zornitza Stark gene: CASP4 was added
gene: CASP4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CASP4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CASP4 were set to 37647624
Phenotypes for gene: CASP4 were set to Hereditary susceptibility to infection, MONDO:0015979, CASP4-related; Susceptibility to meliodiosis
Review for gene: CASP4 was set to RED
Added comment: Single patient with severe disease secondary to B. pseudomallei requiring ECMO. Adjunctive IFN-γ administration as replacement for its failed induction by IL-18 promptly led to clearance of B. pseudomallei and subsequent weaning of support. Novel homozygous missense mutation in CASP4, at exon 7 c.1030C > T. Peripheral blood mononuclear cells (PBMC) of the patient and her parents showed reduced IFN-γ production, notably to IL-12 stimulation, and decreased IL-18 in response to LPS and increased IL-1B. Cloned cells show impacts on CASP4 activation and pyroptosis.
Sources: Expert Review
Mendeliome v1.1228 IL36RN Zornitza Stark Phenotypes for gene: IL36RN were changed from Psoriasis 14, pustular, MIM# 614204 to Psoriasis 14, pustular, MIM# 614204; Autoinflammatory syndrome, MONDO:0019751, IL36RN-related
Mendeliome v1.1227 IL36RN Zornitza Stark Mode of inheritance for gene: IL36RN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1226 IL36RN Zornitza Stark edited their review of gene: IL36RN: Added comment: Monoallelic disease: Multiple patients with systemic inflammation with monoallelic variants in IL36RN suggesting a gene dosage effect whereby GPP onset is significantly delayed in subjects with monoallelic mutations but still at high risk of systemic inflammation.; Changed publications: 21848462, 21839423, 22903787, 23648549, 25458002; Changed phenotypes: Psoriasis 14, pustular, MIM# 614204, Autoinflammatory syndrome, MONDO:0019751, IL36RN-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1226 SNAPC4 Zornitza Stark Phenotypes for gene: SNAPC4 were changed from Neurodevelopmental disorder (MONDO#0700092), SNAPC4-related to Neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction, MIM# 620515
Mendeliome v1.1225 PLCG1 Zornitza Stark Phenotypes for gene: PLCG1 were changed from Autoinflammatory syndrome, MONDO:0019751, PLCG1-related; Immune dysregulation to Immune dysregulation, autoimmunity, and autoinflammation, MIM# 620514
Mendeliome v1.1224 PLCG1 Zornitza Stark edited their review of gene: PLCG1: Changed phenotypes: Immune dysregulation, autoimmunity, and autoinflammation, MIM# 620514
Mendeliome v1.1224 CPEB1 Zornitza Stark Phenotypes for gene: CPEB1 were changed from Primary ovarian insufficiency to Primary ovarian insufficiency, MONDO:0005387, CPEB1-related
Mendeliome v1.1223 CPA1 Zornitza Stark Phenotypes for gene: CPA1 were changed from Susceptibility to chronic pancreatitis; Hereditary pancreatitis to Hereditary pancreatitis, MONDO:0008185, CPA1-related
Mendeliome v1.1222 CPA1 Zornitza Stark edited their review of gene: CPA1: Changed phenotypes: Hereditary pancreatitis, MONDO:0008185, CPA1-related
Mendeliome v1.1222 CNTN6 Zornitza Stark Phenotypes for gene: CNTN6 were changed from Intellectual disability; autism; Tourette syndrome; schizophrenia to Neurodevelopmental disorder, MONDO:0700092, CNTN6-related
Mendeliome v1.1221 CNTN6 Zornitza Stark edited their review of gene: CNTN6: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, CNTN6-related
Mendeliome v1.1221 CNTN3 Zornitza Stark Phenotypes for gene: CNTN3 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, CNTN3-related
Mendeliome v1.1220 CNTN2 Zornitza Stark Phenotypes for gene: CNTN2 were changed from Epilepsy to Epilepsy, MONDO:0015653, CNTN2-related
Mendeliome v1.1219 CNKSR1 Zornitza Stark Phenotypes for gene: CNKSR1 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, CNKSR1-related
Mendeliome v1.1218 CMAS Zornitza Stark Phenotypes for gene: CMAS were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, CMAS-related
Mendeliome v1.1217 CHST8 Zornitza Stark Phenotypes for gene: CHST8 were changed from Peeling skin syndrome to Peeling skin syndrome, MONDO:0019347, CHST8-realted
Mendeliome v1.1216 NCKAP1 Ain Roesley Phenotypes for gene: NCKAP1 were changed from Intellectual disability; autism to Neurodevelopmental disorder (MONDO#0700092)​​​​​​​, NCKAP1-related
Mendeliome v1.1215 PPP1R13L Zornitza Stark Phenotypes for gene: PPP1R13L were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042 - PPP1R13L-related; Dilated cardiomyopathy, onset in infancy to Arrhythmogenic cardiomyopathy with or without ectodermal abnormalities, MIM#620519
Mendeliome v1.1214 PPP1R13L Zornitza Stark edited their review of gene: PPP1R13L: Changed phenotypes: Arrhythmogenic cardiomyopathy with or without ectodermal abnormalities, MIM#620519
Mendeliome v1.1214 DEPDC5 Zornitza Stark Phenotypes for gene: DEPDC5 were changed from Epilepsy, familial focal, with variable foci 1, MIM#604364 to Epilepsy, familial focal, with variable foci 1, MIM#604364; Developmental and epileptic encephalopathy 111, MIM# 620504
Mendeliome v1.1213 CELA3B Zornitza Stark Phenotypes for gene: CELA3B were changed from Chronic pancreatitis to Chronic pancreatitis, MONDO:0008185, CELA3B-related
Mendeliome v1.1212 CDK5R1 Zornitza Stark Phenotypes for gene: CDK5R1 were changed from Intellectual disability; autism to Neurodevelopmental disorder, MONDO:0700092, CDK5R1-related
Mendeliome v1.1211 CDK5R1 Zornitza Stark edited their review of gene: CDK5R1: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, CDK5R1-related
Mendeliome v1.1211 ASTN2 Zornitza Stark Phenotypes for gene: ASTN2 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, ASTN2-related
Mendeliome v1.1210 ASTN2 Zornitza Stark Publications for gene: ASTN2 were set to 28940097
Mendeliome v1.1209 CBY1 Zornitza Stark Phenotypes for gene: CBY1 were changed from intellectual disability; cerebellar ataxia; molar tooth sign; polydactyly; Joubert syndrome to Joubert syndrome, MONDO:0018772, CBY1-related
Mendeliome v1.1208 CAPZA2 Zornitza Stark Phenotypes for gene: CAPZA2 were changed from intellectual disability to Neurodevelopmental disorder, MONDO:0700092, CAPZA2-related
Mendeliome v1.1207 CACNB1 Zornitza Stark Phenotypes for gene: CACNB1 were changed from Malignant hyperthermia susceptibility to Malignant hyperthermia susceptibility, MONDO:0800188, CACNB1-related
Mendeliome v1.1206 CACNB1 Zornitza Stark edited their review of gene: CACNB1: Changed rating: RED; Changed phenotypes: Malignant hyperthermia susceptibility, MONDO:0800188, CACNB1-related
Mendeliome v1.1206 C1orf194 Zornitza Stark Phenotypes for gene: C1orf194 were changed from Charcot-Marie-Tooth disease, intermediate or demyelinating to Charcot-Marie-Tooth disease, intermediate or demyelinating, MONDO:0015626, C1orf194-related
Mendeliome v1.1205 C1orf194 Zornitza Stark edited their review of gene: C1orf194: Changed rating: AMBER; Changed phenotypes: Charcot-Marie-Tooth disease, intermediate or demyelinating, MONDO:0015626, C1orf194; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1205 BLOC1S1 Zornitza Stark Phenotypes for gene: BLOC1S1 were changed from severe intellectual disability; severe global developmental delay; epilepsy to Neurodevelopmental disorder, MONDO:0700092, BLOC1S1-related
Mendeliome v1.1204 BLOC1S1 Zornitza Stark edited their review of gene: BLOC1S1: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, BLOC1S1-related
Mendeliome v1.1204 BET1 Zornitza Stark Phenotypes for gene: BET1 were changed from Muscular dystrophy; Epilepsy to Muscular dystrophy, MONDO:0019950, BET1-related; Epilepsy
Mendeliome v1.1203 BCL9L Zornitza Stark Phenotypes for gene: BCL9L were changed from Heterotaxy; Congenital Heart Disease to Heterotaxy syndrome, MONDO:0018677, BCL9L-related
Mendeliome v1.1202 BCL9L Zornitza Stark edited their review of gene: BCL9L: Changed phenotypes: Heterotaxy syndrome, MONDO:0018677, BCL9L
Mendeliome v1.1202 B3GNT2 Zornitza Stark Phenotypes for gene: B3GNT2 were changed from Muscular dystrophy-dystroglycanopathy to Muscular dystrophy-dystroglycanopathy, MONDO:0018276, B3GNT2-related
Mendeliome v1.1201 B3GNT2 Zornitza Stark edited their review of gene: B3GNT2: Changed phenotypes: Muscular dystrophy-dystroglycanopathy, MONDO:0018276, B3GNT2-related
Mendeliome v1.1201 AXL Zornitza Stark Phenotypes for gene: AXL were changed from Kallman syndrome; normosmic idiopathic hypogonadotropic hypogonadism to Kallman syndrome, MONDO:0018800, AXL-related; normosmic idiopathic hypogonadotropic hypogonadism
Mendeliome v1.1200 ATXN2L Zornitza Stark Phenotypes for gene: ATXN2L were changed from macrocephaly; intellectual disability to Neurodevelopmental disorder, MONDO:0700092, ATXN2L-related
Mendeliome v1.1199 ATRIP Zornitza Stark Phenotypes for gene: ATRIP were changed from Seckel Syndrome to Seckel Syndrome, MONDO:0019342, ATRIP-related
Mendeliome v1.1198 ATP2B4 Zornitza Stark Phenotypes for gene: ATP2B4 were changed from Hereditary spastic paraplegia to Hereditary spastic paraplegia, MONDO:0019064, ATP2B4-related
Mendeliome v1.1197 ASTN2 Zornitza Stark Mode of inheritance for gene: ASTN2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1196 ASTN2 Zornitza Stark edited their review of gene: ASTN2: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1196 ASTN2 Zornitza Stark edited their review of gene: ASTN2: Changed publications: 28940097, 34412080, 27138430
Mendeliome v1.1196 ASTN2 Zornitza Stark edited their review of gene: ASTN2: Added comment: Rare CNVs also reported.; Changed publications: 28940097, 34412080
Mendeliome v1.1196 ASTN2 Zornitza Stark edited their review of gene: ASTN2: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ASTN2-related
Mendeliome v1.1196 ASTN1 Zornitza Stark Phenotypes for gene: ASTN1 were changed from Polymicrogyria; hypoplastic corpus callosum to Cerebral malformation, MONDO:0016054, ASTN1-related
Mendeliome v1.1195 ASTN1 Zornitza Stark edited their review of gene: ASTN1: Changed phenotypes: Cerebral malformation, MONDO:0016054, ASTN1-related
Mendeliome v1.1195 ARIH1 Zornitza Stark Phenotypes for gene: ARIH1 were changed from Thoracic aortic aneurysm to Thoracic aortic aneurysm, MONDO:0005396, ARIH1-related
Mendeliome v1.1194 ARHGAP29 Zornitza Stark Phenotypes for gene: ARHGAP29 were changed from Cleft palate; cleft lip with or without cleft palate to Clefting disorder, MONDO:0000358, ARHGAP29-related
Mendeliome v1.1193 ARHGAP29 Zornitza Stark edited their review of gene: ARHGAP29: Changed phenotypes: Clefting disorder, MONDO:0000358, ARHGAP29-related
Mendeliome v1.1193 ARHGAP24 Zornitza Stark Phenotypes for gene: ARHGAP24 were changed from FSGS to FSGS, MONDO:0005363, ARHGAP24-related
Mendeliome v1.1192 ARHGAP24 Zornitza Stark edited their review of gene: ARHGAP24: Changed phenotypes: FSGS, MONDO:0005363, ARHGAP24-related
Mendeliome v1.1192 ARFGEF3 Zornitza Stark Phenotypes for gene: ARFGEF3 were changed from Dystonia to Dystonia, MONDO:0044807, ARFGEF3-related
Mendeliome v1.1191 ARF3 Zornitza Stark Phenotypes for gene: ARF3 were changed from Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system to Neurodevelopmental disorder, MONDO:0700092, ARF3-related
Mendeliome v1.1190 ARAP3 Zornitza Stark Phenotypes for gene: ARAP3 were changed from Lymphoedema to Lymphoedema, MONDO:0019297, ARAP3-related
Mendeliome v1.1189 ARAP3 Zornitza Stark edited their review of gene: ARAP3: Changed phenotypes: Lymphoedema, MONDO:0019297, ARAP3-related
Mendeliome v1.1189 MCCC1 Bryony Thompson Publications for gene: MCCC1 were set to 27604308; 11170888; 31730530
Mendeliome v1.1188 MCCC1 Bryony Thompson reviewed gene: MCCC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36822454, 31730530; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 1 deficiency MIM#210200, Organic acidurias; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1188 MCCC1 Bryony Thompson Deleted their review
Mendeliome v1.1188 AP1B1 Zornitza Stark Phenotypes for gene: AP1B1 were changed from Intellectual disability; enteropathy; deafness; ichthyosis; keratoderma to Keratitis-ichthyosis-deafness syndrome, autosomal recessive, MIM# 242150
Mendeliome v1.1187 AP1B1 Zornitza Stark edited their review of gene: AP1B1: Changed phenotypes: Keratitis-ichthyosis-deafness syndrome, autosomal recessive, MIM# 242150
Mendeliome v1.1187 ANKZF1 Zornitza Stark Phenotypes for gene: ANKZF1 were changed from Infantile-onset inflammatory bowel disease to Infantile-onset inflammatory bowel disease, MONDO:0005265, ANKZF1-related
Mendeliome v1.1186 ANKRD31 Zornitza Stark Phenotypes for gene: ANKRD31 were changed from Premature ovarian failure to Premature ovarian failure, MONDO:0019852, ANKRD31-related
Mendeliome v1.1185 AMBRA1 Zornitza Stark Phenotypes for gene: AMBRA1 were changed from Neural tube defects to Neural tube defects, susceptibility to, MONDO:0020705, AMBRA1-related
Mendeliome v1.1184 ALPI Zornitza Stark Phenotypes for gene: ALPI were changed from Inflammatory bowel disease to Inflammatory bowel disease, MONDO:0005265, ALPI-related
Mendeliome v1.1183 ALPI Zornitza Stark edited their review of gene: ALPI: Changed phenotypes: Inflammatory bowel disease, MONDO:0005265, ALPI-related
Mendeliome v1.1183 ALG10 Zornitza Stark Phenotypes for gene: ALG10 were changed from Progressive myoclonus epilepsy; CDG to Congenital disorder of glycosylation, MONDO:0015286, ALG10-related
Mendeliome v1.1182 ALG10 Zornitza Stark edited their review of gene: ALG10: Changed phenotypes: Congenital disorder of glycosylation, MONDO:0015286, ALG10-related
Mendeliome v1.1182 AKR1E2 Zornitza Stark Phenotypes for gene: AKR1E2 were changed from congenital cataracts to Cataract, MONDO:0005129, AKR1E2-related
Mendeliome v1.1181 AKR1E2 Zornitza Stark edited their review of gene: AKR1E2: Changed phenotypes: Cataract, MONDO:0005129, AKR1E2-related
Mendeliome v1.1181 AKNA Zornitza Stark Phenotypes for gene: AKNA were changed from Primary ciliary dyskinesia to Primary ciliary dyskinesia, MONDO:0016575, AKNA-related
Mendeliome v1.1180 AKNA Zornitza Stark reviewed gene: AKNA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia, MONDO:0016575, AKNA-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1180 AKAP6 Zornitza Stark Phenotypes for gene: AKAP6 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, AKAP6-related
Mendeliome v1.1179 AKAP6 Zornitza Stark edited their review of gene: AKAP6: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, AKAP6-related
Mendeliome v1.1179 AGO3 Zornitza Stark Phenotypes for gene: AGO3 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, AGO3-related
Mendeliome v1.1178 AGMO Zornitza Stark Phenotypes for gene: AGMO were changed from microcephaly; intellectual disability; epilepsy to Neurodevelopmental disorder, MONDO:0700092, AGMO-related
Mendeliome v1.1177 AGMO Zornitza Stark reviewed gene: AGMO: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, AGMO-related; Mode of inheritance: None
Mendeliome v1.1177 ACTL6A Zornitza Stark Phenotypes for gene: ACTL6A were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, ACTL6A-related
Mendeliome v1.1176 ACTL6A Zornitza Stark edited their review of gene: ACTL6A: Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, ACTL6A-related
Mendeliome v1.1176 ACER3 Zornitza Stark Classified gene: ACER3 as Green List (high evidence)
Mendeliome v1.1176 ACER3 Zornitza Stark Gene: acer3 has been classified as Green List (High Evidence).
Mendeliome v1.1175 ACADL Zornitza Stark Phenotypes for gene: ACADL were changed from Pulmonary surfactant dysfunction to Hereditary pulmonary alveoral proteinosis, MONDO:0012580, ACADL-related
Mendeliome v1.1174 ACADL Zornitza Stark edited their review of gene: ACADL: Changed phenotypes: Hereditary pulmonary alveoral proteinosis, MONDO:0012580, ACADL-related
Mendeliome v1.1174 SEMA3E Zornitza Stark Publications for gene: SEMA3E were set to 15235037; 31691538; 31464029
Mendeliome v1.1173 SEMA3E Lucy Spencer reviewed gene: SEMA3E: Rating: AMBER; Mode of pathogenicity: None; Publications: 15235037, 31691538, 31464029, 35628442, 32441320; Phenotypes: CHARGE syndrome MONDO:0008965, SEMA3E-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1173 SCAF4 Zornitza Stark Phenotypes for gene: SCAF4 were changed from Mild intellectual disability; seizures; behavioral abnormalities to Fliedner-Zweier syndrome, MIM#620511
Mendeliome v1.1172 SCAF4 Zornitza Stark reviewed gene: SCAF4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fliedner-Zweier syndrome, MIM#620511; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1172 NR2F2 Zornitza Stark Phenotypes for gene: NR2F2 were changed from 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779 to Krithika Murali (Victorian Clinical Genetics Services) 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779 Current 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779 Edit; 46,XX sex reversal 5 - MIM#618901; Congenital heart defects, multiple types, 4 - MIM#615779
Mendeliome v1.1171 NR2F2 Zornitza Stark Publications for gene: NR2F2 were set to 24702954; 29478779; 31687637; 27363585; 29222010; 29663647
Mendeliome v1.1170 NR2F2 Zornitza Stark reviewed gene: NR2F2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37500725; Phenotypes: Syndromic disease, MONDO:0002254, NR2F2-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1170 DBR1 Zornitza Stark Phenotypes for gene: DBR1 were changed from {Encephalitis, acute, infection (viral)-induced, susceptibility to, 11}, MIM# 619441; Viral infections of the brainstem; Ichthyosis (MONDO#0019269), DBR1-related to {Encephalitis, acute, infection (viral)-induced, susceptibility to, 11}, MIM# 619441; Viral infections of the brainstem; Xerosis and growth failure with immune and pulmonary dysfunction syndrome, MIM# 620510
Mendeliome v1.1169 TRAC Zornitza Stark Tag technically challenging tag was added to gene: TRAC.
Mendeliome v1.1169 KLK11 Zornitza Stark Marked gene: KLK11 as ready
Mendeliome v1.1169 KLK11 Zornitza Stark Gene: klk11 has been classified as Green List (High Evidence).
Mendeliome v1.1169 KLK11 Zornitza Stark Classified gene: KLK11 as Green List (high evidence)
Mendeliome v1.1169 KLK11 Zornitza Stark Gene: klk11 has been classified as Green List (High Evidence).
Mendeliome v1.1168 KLK11 Zornitza Stark gene: KLK11 was added
gene: KLK11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: KLK11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLK11 were set to 36689511; 37212630
Phenotypes for gene: KLK11 were set to Ichthyosis with erythrokeratoderma, MIM# 620507
Review for gene: KLK11 was set to GREEN
Added comment: Four families reported: one multiplex with variant segregating with disease in 4 affected and 4 unaffected individuals. Three additional families with de novo variants.
Sources: Literature
Mendeliome v1.1167 GABBR1 Zornitza Stark Phenotypes for gene: GABBR1 were changed from Neurodevelopmental disorder, GABBR1-related, MONDO:0700092 to Neurodevelopmental disorder with language delay and variable cognitive abnormalities, MIM#620502
Mendeliome v1.1166 GABBR1 Zornitza Stark edited their review of gene: GABBR1: Changed phenotypes: Neurodevelopmental disorder with language delay and variable cognitive abnormalities, MIM#620502
Mendeliome v1.1166 FTCD Bryony Thompson Publications for gene: FTCD were set to 27604308; 12815595
Mendeliome v1.1165 FTCD Bryony Thompson edited their review of gene: FTCD: Changed publications: http://iembase.com/disorder/47
Mendeliome v1.1165 FTCD Bryony Thompson changed review comment from: Well-established gene-disease association (see OMIM entry). Glutamate formiminotransferase deficiency is classified as a metabolic disorder by the NIH GARD (https://rarediseases.info.nih.gov/diseases/diseases-by-category/14/metabolic-disorders), and is an inborn error of amino acid metabolism.
Sources: NHS GMS; to: Glutamate formiminotransferase deficiency is classified as a benign form of folate metabolism disorder and an inborn error of amino acid metabolism without clinically significant phenotype (http://iembase.com/disorder/47).
Mendeliome v1.1165 MAP1B Zornitza Stark Phenotypes for gene: MAP1B were changed from Intellectual disability; seizures; PVNH; dysmorphic features; Periventricular nodular heterotopia 9, MIM# 618918 to Intellectual disability; seizures; PVNH; dysmorphic features; Periventricular nodular heterotopia 9, MIM# 618918; Deafness, autosomal dominant 83, MIM# 619808
Mendeliome v1.1164 MAP1B Zornitza Stark edited their review of gene: MAP1B: Added comment: At least 3 families reported with isolated deafness and mono-allelic variants.; Changed phenotypes: Intellectual disability, seizures, PVNH, dysmorphic features, Periventricular nodular heterotopia 9, MIM# 618918, Deafness, autosomal dominant 83, MIM# 619808
Mendeliome v1.1164 GJA4 Zornitza Stark Marked gene: GJA4 as ready
Mendeliome v1.1164 GJA4 Zornitza Stark Gene: gja4 has been classified as Green List (High Evidence).
Mendeliome v1.1164 GJA4 Zornitza Stark Classified gene: GJA4 as Green List (high evidence)
Mendeliome v1.1164 GJA4 Zornitza Stark Gene: gja4 has been classified as Green List (High Evidence).
Mendeliome v1.1163 GJA4 Zornitza Stark gene: GJA4 was added
gene: GJA4 was added to Mendeliome. Sources: Expert Review
somatic tags were added to gene: GJA4.
Mode of inheritance for gene: GJA4 was set to Other
Publications for gene: GJA4 were set to 33912852
Phenotypes for gene: GJA4 were set to Cavernous hemangioma, MONDO:0003155, GJA4-related
Review for gene: GJA4 was set to GREEN
Added comment: Recurrent somatic GJA4 c.121G>T (p.Gly41Cys) mutation as a driver of hepatic (n=12) and cutaneous (n=3) vascular malformations. Induced changes in cell morphology and activated serum/glucocorticoid-regulated kinase 1 (SGK1), a serine/threonine kinase known to regulate cell proliferation and apoptosis, via non-canonical activation, in lentiviral transduction of primary human endothelial cells.
Sources: Expert Review
Mendeliome v1.1162 COL4A3BP Zornitza Stark Phenotypes for gene: COL4A3BP were changed from Mental retardation, autosomal dominant 34, MIM# 616351 to Intellectual developmental disorder 34 (MIM#616351)
Mendeliome v1.1161 COL4A3BP Zornitza Stark Publications for gene: COL4A3BP were set to 25533962
Mendeliome v1.1160 COL4A3BP Zornitza Stark Mode of pathogenicity for gene: COL4A3BP was changed from to Other
Mendeliome v1.1159 DBR1 Zornitza Stark Phenotypes for gene: DBR1 were changed from {Encephalitis, acute, infection (viral)-induced, susceptibility to, 11}, MIM# 619441; Viral infections of the brainstem to {Encephalitis, acute, infection (viral)-induced, susceptibility to, 11}, MIM# 619441; Viral infections of the brainstem; Ichthyosis (MONDO#0019269), DBR1-related
Mendeliome v1.1158 DBR1 Zornitza Stark edited their review of gene: DBR1: Added comment: PMID: 37656279:
- A homozygous missense as a founder recessive DBR1 variant in four consanguineous families.
- Total of 7 affected children. WES done for one proband from each family.
- Consistent features include prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation (collodion membrane, severe skin peeling and xerosis), and death before the first year of life.
- RNA and protein studies using fibroblasts derived from a patient are supportive of pathogenicity: RNA-seq, rt-qPCR and western blotting, showing marked reduction of DBR1 level and intronic RNA lariat accumulation in the patient sample.
- Haplotype analysis revealed that the four families all share a haplotype extending at least 2.27 Mb around the c.200A>G p.(Tyr67Cys) DBR1 founder variant.
- Authors proposed this is a novel DBR1-related developmental disorder that is distinct from DBR1-related encephalitis susceptibility, and highlighted the apparent lack of correlation with the degree of DBR1 deficiency.; Changed publications: 29474921, 37656279; Changed phenotypes: {Encephalitis, acute, infection (viral)-induced, susceptibility to, 11}, MIM# 619441, Viral infections of the brainstem, Ichthyosis (MONDO#0019269), DBR1-related
Mendeliome v1.1158 APOO Zornitza Stark Phenotypes for gene: APOO were changed from Developmental delay; Lactic acidosis; Muscle weakness; Hypotonia; Repetitive infections; Cognitive impairment; Autistic behaviour to Mitochondrial disease, MONDO:0044970, APOO-related; Developmental delay; Lactic acidosis; Muscle weakness; Hypotonia; Repetitive infections; Cognitive impairment; Autistic behaviour
Mendeliome v1.1157 APOO Zornitza Stark Publications for gene: APOO were set to 32439808
Mendeliome v1.1156 APOO Zornitza Stark edited their review of gene: APOO: Added comment: PMID: 37649161
1 family, 2 individuals (male & female) with same NMD variant c.532G>T (p.E178*), maternally inherited (mother unaffected).

Both died before 18 months of age with partial agenesis of the corpus callosum, bilateral congenital cataract, hypothyroidism, and severe immune deficiencies.
Other phenotypes included partial syndactyly of the 2nd and 3rd toes, wrinkled palm, and sole skin.

Functional studies included site directed mutagenesis. This mutation resulted in a highly unstable and degradation
prone MIC26 protein, yet the remaining minute amounts of mutant MIC26 correctly localized to mitochondria and
interacted physically with other MICOS subunits. MIC26 KO cells expressing MIC26 harboring the respective APOO/MIC26 mutation showed mitochondria with perturbed cristae architecture and fragmented morphology resembling MIC26 KO cells.; Changed publications: 37649161; Changed phenotypes: Mitochondrial disease, MONDO:0044970, APOO-related, Developmental delay, Lactic acidosis, Muscle weakness, Hypotonia, Repetitive infections, Cognitive impairment, Autistic behaviour
Mendeliome v1.1156 RAB5C Rylee Peters changed review comment from: 12 individuals with nine different heterozygous de novo variants in RAB5C.
9 with missense, 1 inframe duplication and 2 stop-gains (clinically more severe).
All has mild-severe ID, 4/12 have epilepsy, 6/12 have macrocephaly (more than 3 SD).
Sources: Literature; to: 12 individuals with nine different heterozygous de novo variants in RAB5C.
9 with missense, 1 inframe duplication and 2 stop-gains (clinically more severe).
All have mild-severe ID, 4/12 have epilepsy, 6/12 have macrocephaly (more than 3 SD).
Sources: Literature
Mendeliome v1.1156 DBR1 Chern Lim reviewed gene: DBR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 37656279; Phenotypes: Ichthyosis (MONDO#0019269), DBR1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1156 CAP2 Zornitza Stark Phenotypes for gene: CAP2 were changed from Dilated cardiomyopathy to Cardiomyopathy, dilated, 2I (MIM#620462)
Mendeliome v1.1155 COL4A3BP Ee Ming Wong changed review comment from: - Thirty-one unrelated individuals with twenty-two distinct missense variants. The majority of variants were de novo.
- Several variants transfected into HeLa cells demonstrated gain of CERT activity
- CERT gain of function in Drosophila melanogaster led to head and brain size defects and impaired locomotor activity, which was corrected by pharmacological inhibition of CERT; to: - current HGNC symbol: CERT1
- Thirty-one unrelated individuals with twenty-two distinct missense variants. The majority of variants were de novo.
- Several variants transfected into HeLa cells demonstrated gain of CERT activity
- CERT gain of function in Drosophila melanogaster led to head and brain size defects and impaired locomotor activity, which was corrected by pharmacological inhibition of CERT
Mendeliome v1.1155 CAP2 Zornitza Stark Publications for gene: CAP2 were set to 30518548
Mendeliome v1.1154 CAP2 Zornitza Stark Classified gene: CAP2 as Green List (high evidence)
Mendeliome v1.1154 CAP2 Zornitza Stark Gene: cap2 has been classified as Green List (High Evidence).
Mendeliome v1.1153 CAP2 Zornitza Stark reviewed gene: CAP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30518548, 33083013, 34862840; Phenotypes: Cardiomyopathy, dilated, 2I (MIM#620462); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1153 COL4A3BP Ee Ming Wong reviewed gene: COL4A3BP: Rating: GREEN; Mode of pathogenicity: Other; Publications: PMID: 36976648; Phenotypes: Intellectual developmental disorder 34 (MIM#616351); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.1153 RAB5C Ain Roesley Marked gene: RAB5C as ready
Mendeliome v1.1153 RAB5C Ain Roesley Gene: rab5c has been classified as Green List (High Evidence).
Mendeliome v1.1153 RAB5C Ain Roesley Classified gene: RAB5C as Green List (high evidence)
Mendeliome v1.1153 RAB5C Ain Roesley Gene: rab5c has been classified as Green List (High Evidence).
Mendeliome v1.1153 RAB5C Ain Roesley Classified gene: RAB5C as Green List (high evidence)
Mendeliome v1.1153 RAB5C Ain Roesley Gene: rab5c has been classified as Green List (High Evidence).
Mendeliome v1.1152 RAB5C Rylee Peters gene: RAB5C was added
gene: RAB5C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RAB5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB5C were set to PMID: 37552066
Phenotypes for gene: RAB5C were set to Neurodevelopmental disorder MONDO:0700092, RAB5C-related
Penetrance for gene: RAB5C were set to Complete
Review for gene: RAB5C was set to GREEN
gene: RAB5C was marked as current diagnostic
Added comment: 12 individuals with nine different heterozygous de novo variants in RAB5C.
9 with missense, 1 inframe duplication and 2 stop-gains (clinically more severe).
All has mild-severe ID, 4/12 have epilepsy, 6/12 have macrocephaly (more than 3 SD).
Sources: Literature
Mendeliome v1.1152 AXIN1 Elena Savva Phenotypes for gene: AXIN1 were changed from Caudal duplication anomaly, MIM# 607864 to Caudal duplication anomaly, MIM# 607864; Syndromic disease, (MONDO:0002254), AXIN1-related
Mendeliome v1.1152 AXIN1 Elena Savva Publications for gene: AXIN1 were set to 9335612
Mendeliome v1.1151 AXIN1 Elena Savva Classified gene: AXIN1 as Green List (high evidence)
Mendeliome v1.1151 AXIN1 Elena Savva Gene: axin1 has been classified as Green List (High Evidence).
Mendeliome v1.1151 AXIN1 Elena Savva Mode of inheritance for gene: AXIN1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1150 AXIN1 Elena Savva Classified gene: AXIN1 as Green List (high evidence)
Mendeliome v1.1150 AXIN1 Elena Savva Gene: axin1 has been classified as Green List (High Evidence).
Mendeliome v1.1149 COL4A3BP Zornitza Stark Tag new gene name tag was added to gene: COL4A3BP.
Mendeliome v1.1149 PPP1R3F Andrew Fennell changed review comment from: Sources: Literature; to: 13 unrelated hemizygous individuals reported with functional evidence
Sources: Literature
Mendeliome v1.1149 PPP1R3F Zornitza Stark Marked gene: PPP1R3F as ready
Mendeliome v1.1149 PPP1R3F Zornitza Stark Gene: ppp1r3f has been classified as Green List (High Evidence).
Mendeliome v1.1149 PPP1R3F Zornitza Stark Classified gene: PPP1R3F as Green List (high evidence)
Mendeliome v1.1149 PPP1R3F Zornitza Stark Gene: ppp1r3f has been classified as Green List (High Evidence).
Mendeliome v1.1148 PPP1R3F Andrew Fennell gene: PPP1R3F was added
gene: PPP1R3F was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPP1R3F was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PPP1R3F were set to 37531237
Phenotypes for gene: PPP1R3F were set to Neurodevelopmental Disorder, MONDO:0700092,PPP1R3F-related
Review for gene: PPP1R3F was set to GREEN
Added comment: Sources: Literature
Mendeliome v1.1148 LAMA3 Bryony Thompson Publications for gene: LAMA3 were set to 7633458; 8530087; 11810295; 10366601
Mendeliome v1.1147 FTH1 Bryony Thompson Publications for gene: FTH1 were set to 11389486; 36778397
Mendeliome v1.1146 FTH1 Bryony Thompson Mode of pathogenicity for gene: FTH1 was changed from None to Other
Mendeliome v1.1145 FTH1 Bryony Thompson Classified gene: FTH1 as Green List (high evidence)
Mendeliome v1.1145 FTH1 Bryony Thompson Added comment: Comment on list classification: Article describing the gene-disease association with neuroferritinopathy now published in HGG advances
Mendeliome v1.1145 FTH1 Bryony Thompson Gene: fth1 has been classified as Green List (High Evidence).
Mendeliome v1.1144 C3 Ain Roesley Phenotypes for gene: C3 were changed from C3 deficiency MIM#613779 to C3 deficiency MIM#613779; C3 deficiency MIM#613779; {Hemolytic uremic syndrome, atypical, susceptibility to, 5}, MIM# 612925
Mendeliome v1.1143 C3 Ain Roesley Publications for gene: C3 were set to 15781264; 1944729; 11813855; 26847111
Mendeliome v1.1143 C3 Ain Roesley Mode of inheritance for gene: C3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1142 C3 Ain Roesley edited their review of gene: C3: Changed phenotypes: C3 deficiency MIM#613779, {Hemolytic uremic syndrome, atypical, susceptibility to, 5}, MIM# 612925
Mendeliome v1.1142 C3 Ain Roesley edited their review of gene: C3: Added comment: Multiple individuals reported with mono-allelic variants and aHUS. At least one report of biallelic variants.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1142 SLC30A7 Zornitza Stark reviewed gene: SLC30A7: Rating: RED; Mode of pathogenicity: None; Publications: 36821639; Phenotypes: Ziegler-Huang syndrome, MIM# 620501; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1142 SOX11 Zornitza Stark Phenotypes for gene: SOX11 were changed from Coffin-Siris syndrome 9, MIM# 615866; Congenital abnormalities of the kidneys and urinary tract to Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, MIM# 615866; Congenital abnormalities of the kidneys and urinary tract
Mendeliome v1.1141 SOX11 Zornitza Stark Publications for gene: SOX11 were set to 29459093; 24886874
Mendeliome v1.1140 SOX11 Zornitza Stark edited their review of gene: SOX11: Added comment: Over 40 additional individuals reported, e.g. PMID 35341651. The phenotype that has emerged over time is distinct from patients with mutations in ARID1B (614556) and Coffin-Siris syndrome-1 (135900). Patients with IDDMOH tend to be microcephalic and have ocular motor apraxia, abnormal eye morphology, or hypogonadotropic hypogonadism.; Changed publications: 29459093, 24886874, 33086258, 33785884, 35642566, 35341651
Mendeliome v1.1140 SOX11 Zornitza Stark edited their review of gene: SOX11: Changed phenotypes: Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, MIM# 615866, Congenital abnormalities of the kidneys and urinary tract
Mendeliome v1.1140 RAP1B Zornitza Stark Phenotypes for gene: RAP1B were changed from RAP1B‐associated syndrome; intellectual disability; microcephaly; thrombocytopaenia to Syndromic disease, MONDO:0002254, RAP1B-related; intellectual disability; microcephaly; thrombocytopaenia
Mendeliome v1.1139 PTCD3 Zornitza Stark Publications for gene: PTCD3 were set to 30607703; 19427859
Mendeliome v1.1138 PTCD3 Zornitza Stark Classified gene: PTCD3 as Green List (high evidence)
Mendeliome v1.1138 PTCD3 Zornitza Stark Gene: ptcd3 has been classified as Green List (High Evidence).
Mendeliome v1.1137 PTCD3 Zornitza Stark edited their review of gene: PTCD3: Added comment: Three additional families reported.; Changed rating: GREEN; Changed publications: 30607703, 19427859, 36450274
Mendeliome v1.1137 MRM2 Zornitza Stark Phenotypes for gene: MRM2 were changed from MELAS-like to Mitochondrial DNA depletion syndrome 17, MIM# 618567
Mendeliome v1.1136 MRM2 Zornitza Stark Classified gene: MRM2 as Green List (high evidence)
Mendeliome v1.1136 MRM2 Zornitza Stark Gene: mrm2 has been classified as Green List (High Evidence).
Mendeliome v1.1135 MRM2 Zornitza Stark edited their review of gene: MRM2: Added comment: Two additional families reported.; Changed rating: GREEN; Changed publications: 28973171, 36002240; Changed phenotypes: Mitochondrial DNA depletion syndrome 17, MIM# 618567
Mendeliome v1.1135 COX5A Zornitza Stark Publications for gene: COX5A were set to 2824752
Mendeliome v1.1134 COX5A Zornitza Stark Classified gene: COX5A as Amber List (moderate evidence)
Mendeliome v1.1134 COX5A Zornitza Stark Gene: cox5a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1133 COX5A Zornitza Stark edited their review of gene: COX5A: Added comment: Second family reported, albeit hmz missense.; Changed rating: AMBER; Changed publications: 35246835, 28247525
Mendeliome v1.1133 CRELD1 Zornitza Stark Phenotypes for gene: CRELD1 were changed from Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217 to Developmental and epileptic encephalopathy, MONDO:0100062, CRELD1-related; Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217
Mendeliome v1.1132 CRELD1 Zornitza Stark Mode of inheritance for gene: CRELD1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1131 CRELD1 Zornitza Stark Classified gene: CRELD1 as Green List (high evidence)
Mendeliome v1.1131 CRELD1 Zornitza Stark Gene: creld1 has been classified as Green List (High Evidence).
Mendeliome v1.1130 CRELD1 Zornitza Stark edited their review of gene: CRELD1: Added comment: Emerging association between bi-alleic variants in CRELD1 and DEE.; Changed rating: GREEN; Changed phenotypes: Developmental and epileptic encephalopathy, MONDO:0100062, CRELD1-related, Atrioventricular septal defect, partial, with heterotaxy syndrome, MIM# 606217; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1130 UBAP2L Zornitza Stark Phenotypes for gene: UBAP2L were changed from Neurodevelopmental disorder, MONDO:0700092, UBAP2L-related to Neurodevelopmental disorder with impaired language, behavioral abnormalities, and dysmorphic facies, MIM# 620494
Mendeliome v1.1129 UBAP2L Zornitza Stark edited their review of gene: UBAP2L: Changed phenotypes: Neurodevelopmental disorder with impaired language, behavioral abnormalities, and dysmorphic facies, MIM# 620494
Mendeliome v1.1129 NEUROG1 Zornitza Stark Marked gene: NEUROG1 as ready
Mendeliome v1.1129 NEUROG1 Zornitza Stark Gene: neurog1 has been classified as Green List (High Evidence).
Mendeliome v1.1129 NEUROG1 Zornitza Stark Classified gene: NEUROG1 as Green List (high evidence)
Mendeliome v1.1129 NEUROG1 Zornitza Stark Gene: neurog1 has been classified as Green List (High Evidence).
Mendeliome v1.1128 SRSF1 Zornitza Stark Phenotypes for gene: SRSF1 were changed from Neurodevelopmental disorder, SRSF1-related MONDO:0700092 to Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, MIM# 620489
Mendeliome v1.1127 SRSF1 Zornitza Stark reviewed gene: SRSF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, MIM# 620489; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1127 TPM4 Zornitza Stark Phenotypes for gene: TPM4 were changed from Macrothrombocytopaenia to Bleeding disorder, platelet-type, 25, MIM# 620486
Mendeliome v1.1126 TPM4 Zornitza Stark edited their review of gene: TPM4: Changed phenotypes: Bleeding disorder, platelet-type, 25, MIM# 620486
Mendeliome v1.1126 PTPRJ Zornitza Stark Phenotypes for gene: PTPRJ were changed from Thrombocytopaenia to Thrombocytopenia 10, MIM# 620484
Mendeliome v1.1125 PTPRJ Zornitza Stark edited their review of gene: PTPRJ: Changed phenotypes: Thrombocytopenia 10, MIM# 620484
Mendeliome v1.1125 THPO Zornitza Stark edited their review of gene: THPO: Added comment: 5 families reported with bi-allelic variants and thrombocytopenia with progression to pancytopenia, aplastic anemia, and bone marrow failure.; Changed publications: 9425899, 10583217, 32150607, 28466964, 24085763, 28559357, 29191945, 36226497; Changed phenotypes: Thrombocythemia 1, MIM# 187950, Thrombocytopenia 9, MIM# 620478, Amegakaryocytic thrombocytopenia, congenital, 2, MIM# 620481; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1125 NEUROG1 Achchuthan Shanmugasundram gene: NEUROG1 was added
gene: NEUROG1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NEUROG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEUROG1 were set to 23419067; 26077850; 33439489; 36647078
Phenotypes for gene: NEUROG1 were set to Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, OMIM:620469
Review for gene: NEUROG1 was set to GREEN
Added comment: There are four unrelated cases reported with global developmental delay/ intellectual disability. Hence, this gene can be added with green rating in the intellectual disability panel.

PMID:23419067 - A homozygous micro deletion of NEUROG1 was identified in a six year-old boy presenting with profound sensorineural deafness, balance disorder, severe disorder of oral motor function, and mild global developmental delay. His IQ was normal.

PMID:26077850 - A homozygous NEUROG1 variant (p.Arg116Leu) was identified in a 12 year-old boy presented with syndromic corneal opacity, mild intellectual disability and absent corneal reflex.

PMID:33439489 - A homozygous loss-of-function variant (p.Glu68Ter) was identified in a 12 year-old boy presenting with hypotonia, global developmental delay, sensorineural hearing loss, and keratoconjunctivitis due to lack of corneal reflex. This patient had a global IQ of 62 at the age of ten.

PMID:36647078 - A female proband was identified with a novel homozygous truncating frameshift variant (p.Thr78ProfsTer122 and was reported with profound global developmental delay, autism spectrum disorder, hearing loss, corneal opacity and no eye blinking. Her sister also had a similar, but less severe phenotype and also harboured the same variant at homozygous state.

This gene has been associated with relevant phenotypes in OMIM (MIM #620469), but not in Gene2Phenotype.
Sources: Literature
Mendeliome v1.1125 STAT5B Zornitza Stark Tag somatic tag was added to gene: STAT5B.
Mendeliome v1.1125 STAT5B Zornitza Stark changed review comment from: Both bi-allelic and mono allelic (GoF) inheritance reported. AD GoF phenotype: increased IgE, growth failure, eczema but no immune defects compared to AR phenotype (modestly decreased T cells, reduced Tregs and function, hypergammaglobulinaemia, increased IgE).; to: Both bi-allelic and mono allelic (GoF) inheritance reported. AD GoF phenotype: increased IgE, growth failure, eczema but no immune defects compared to AR phenotype (modestly decreased T cells, reduced Tregs and function, hypergammaglobulinaemia, increased IgE).

Somatic variants also reported.
Mendeliome v1.1125 RRM2B Zornitza Stark Mode of inheritance for gene: RRM2B was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1124 PPOX Zornitza Stark Phenotypes for gene: PPOX were changed from Porphyria variegata , MIM#176200 to Porphyria variegata , MIM#176200; Variegate porphyria, childhood-onset, MIM# 620483
Mendeliome v1.1123 PPOX Zornitza Stark Publications for gene: PPOX were set to 12357337; 32247286; 23324528; 27982422
Mendeliome v1.1122 PPOX Zornitza Stark Mode of inheritance for gene: PPOX was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1121 PPOX Zornitza Stark edited their review of gene: PPOX: Added comment: Bi-allelic variants cause childhood onset disease.; Changed publications: 12357337, 32247286, 23324528, 27982422, 9811936, 11286631, 33159949; Changed phenotypes: Porphyria variegata , MIM#176200, Variegate porphyria, childhood-onset, MIM# 620483; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1121 THPO Zornitza Stark Phenotypes for gene: THPO were changed from Thrombocythemia 1, MIM# 187950 to Thrombocythemia 1, MIM# 187950; Thrombocytopenia 9, MIM# 620478
Mendeliome v1.1120 THPO Zornitza Stark Publications for gene: THPO were set to 9425899; 10583217
Mendeliome v1.1119 THPO Zornitza Stark edited their review of gene: THPO: Added comment: Thrombocytopenia: 5 unrelated families reported.; Changed publications: 9425899, 10583217, 32150607, 28466964; Changed phenotypes: Thrombocythemia 1, MIM# 187950, Thrombocytopenia 9, MIM# 620478
Mendeliome v1.1119 ACTB Zornitza Stark Phenotypes for gene: ACTB were changed from Baraitser-Winter syndrome 1 243310; ACTB-related neurodevelopment disorder to Baraitser-Winter syndrome 1 243310; Thrombocytopenia 8, with dysmorphic features and developmental delay, MIM# 620475; ACTB-related neurodevelopment disorder
Mendeliome v1.1118 ACTB Zornitza Stark reviewed gene: ACTB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Thrombocytopenia 8, with dysmorphic features and developmental delay, MIM# 620475; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1118 APOL1 Zornitza Stark Classified gene: APOL1 as Amber List (moderate evidence)
Mendeliome v1.1118 APOL1 Zornitza Stark Gene: apol1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1117 APOL1 Zornitza Stark edited their review of gene: APOL1: Added comment: Assigned Definitive gene-disease validity by the ClinGen Glomerulopathy GCEP - Classification - 09/28/2021
Increased risk of kidney and glomerular diseases in persons carrying two of the risk alleles in this gene: G1/G1, G2/G2 and compound heterozygous G1/G2.
PMID: 20647424 - first study to identify G1 & G2 alleles associated with risk of renal disease. Comparing participants with zero or 1 risk allele of APOL1 to participants with 2 risk alleles provided an odds ratio for FSGS of 10.5 (CI, 6.0-18.4). This analysis supported a completely recessive pattern of inheritance.
PMID: 25993319 - only G1 and G2 confer renal risk, and other common and rare APOL1 missense variants, including the archaic G3 haplotype, do not contribute to sporadic FSGS and HIVAN
rs73885319 (G1) OR 9.66, p=9.97E-25
rs60910145 (G1) OR 9.75, p=9.04E-24
rs71785313 (G2) OR 5.69, p=3.39E-06
2 APOL1 risk alleles OR 18.31, p=3.31E-58
PMID: 34350953 - recessive gain-of-function toxicity mouse model recapitulates human kidney disease
G1:
p.Ser342Gly, AFR/AA gnomAD v2.1 AF 0.2276 (5,671/24,920 alleles, 687 homozygotes)
p.Ile384Met, AFR/AA gnomAD v2.1 AF 0.2278 (5,487/24,082 alleles, 662 homozygotes)
G2:
p.Asn388_Tyr389del, AFR/AA gnomAD v2.1 AF 0.1402(3,402/24,268 alleles, 224 homozygotes

AMBER status due to these being susceptibility alleles, and evidence being limited to these specific variants.; Changed rating: AMBER
Mendeliome v1.1117 GOSR2 Achchuthan Shanmugasundram changed review comment from: Four children from two sibships from an extended consanguineous Palestinian family were reported with congenital profound hearing loss, whereas the parents of both sibships are first cousins with normal hearing. The families reported occasional febrile seizures in infancy for each of the deaf children, but these did not persist into adolescence. These affected children were identified with autosomal recessive GOSR2 variant, c.1A > C, p.Met1Leu. This variant appeared once in the gnomAD database, as a heterozygote, and not in any of ~2000 in-house controls of Palestinian ancestry.

All previously reported cases with biallelic GOSR2 variants had normal hearing and hence the differences in translation efficiency due to the effect of this variant may be responsible for this hearing loss phenotype (PMID:37074134).; to: This gene should be added in 'Deafness_IsolatedAndComplex' panel with red rating.

Four children from two sibships from an extended consanguineous Palestinian family were reported with congenital profound hearing loss, whereas the parents of both sibships are first cousins with normal hearing. The families reported occasional febrile seizures in infancy for each of the deaf children, but these did not persist into adolescence. These affected children were identified with autosomal recessive GOSR2 variant, c.1A > C, p.Met1Leu. This variant appeared once in the gnomAD database, as a heterozygote, and not in any of ~2000 in-house controls of Palestinian ancestry.

All previously reported cases with biallelic GOSR2 variants had normal hearing and hence the differences in translation efficiency due to the effect of this variant may be responsible for this hearing loss phenotype (PMID:37074134).
Mendeliome v1.1117 GOSR2 Achchuthan Shanmugasundram reviewed gene: GOSR2: Rating: RED; Mode of pathogenicity: None; Publications: 37074134; Phenotypes: hearing loss, autosomal recessive, MONDO:0019588; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1117 GFI1 Zornitza Stark Tag treatable tag was added to gene: GFI1.
Mendeliome v1.1117 CORO1A Zornitza Stark Tag treatable tag was added to gene: CORO1A.
Mendeliome v1.1117 CD70 Zornitza Stark Tag treatable tag was added to gene: CD70.
Mendeliome v1.1117 CD40 Zornitza Stark Tag treatable tag was added to gene: CD40.
Mendeliome v1.1117 DDRGK1 Ain Roesley Marked gene: DDRGK1 as ready
Mendeliome v1.1117 DDRGK1 Ain Roesley Gene: ddrgk1 has been classified as Green List (High Evidence).
Mendeliome v1.1117 DDRGK1 Ain Roesley Classified gene: DDRGK1 as Green List (high evidence)
Mendeliome v1.1117 DDRGK1 Ain Roesley Gene: ddrgk1 has been classified as Green List (High Evidence).
Mendeliome v1.1116 DDRGK1 Ain Roesley gene: DDRGK1 was added
gene: DDRGK1 was added to Mendeliome. Sources: Literature
founder tags were added to gene: DDRGK1.
Mode of inheritance for gene: DDRGK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDRGK1 were set to 28263186; 35377455; 35670300; 36243336
Phenotypes for gene: DDRGK1 were set to Spondyloepimetaphyseal dysplasia, Shohat type (MIM#602557)
Review for gene: DDRGK1 was set to GREEN
gene: DDRGK1 was marked as current diagnostic
Added comment: RNA and protein studies performed for the splice variant. These two variants likely represents founder variants

PMID:28263186 reported six individuals from three different families of Iraqi Jewish descent (three patients from family 1 and one individual each from families 2-4) identified with homozygous c.408+1G>A donor splice site loss-of-function mutation in DDRGK1 and presented with Shohat-type spondyloepimetaphyseal dysplasia (SEMD). It is a skeletal dysplasia that affects cartilage development.

PMID: 35670300 reported two unrelated cases of Moroccan descent identified with homozygous missense variant c.406G>A and presented with SEMD. PMID:36243336 reported an Omani female patient identified with the same homozygous variant as the Iraqi cases and was reported with SEMD.

In addition, studies on both zebrafish and mouse models confirms the physiological role of DDRGK1 in the development and maintenance of the growth plate cartilage and deficiency of DDRGK1 recapitulate the clinical phenotype of short stature and joint abnormalities observed in patients with Shohat type SEMD (PMID:28263186; PMID:35377455).
Sources: Literature
Mendeliome v1.1115 FBXO31 Zornitza Stark Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979; Cerebral palsy, MONDO:0006497, FBXO31-related; Spastic-dystonic cerebral palsy, intellectual disability, de novo dominant to Intellectual developmental disorder, autosomal recessive 45 (MIM#615979; Cerebral palsy, MONDO:0006497, FBXO31-related; Spastic-dystonic cerebral palsy, intellectual disability, de novo dominant
Mendeliome v1.1114 FBXO31 Zornitza Stark Phenotypes for gene: FBXO31 were changed from Mental retardation, autosomal recessive 45, MIM#615979; Spastic-dystonic cerebral palsy, intellectual disability, de novo dominant to Mental retardation, autosomal recessive 45, MIM#615979; Cerebral palsy, MONDO:0006497, FBXO31-related; Spastic-dystonic cerebral palsy, intellectual disability, de novo dominant
Mendeliome v1.1113 FBXO31 Zornitza Stark Publications for gene: FBXO31 were set to 24623383; 32989326
Mendeliome v1.1112 ATP6V0C Zornitza Stark Phenotypes for gene: ATP6V0C were changed from Epilepsy; Intellectual Disability; microcephaly to Epilepsy, early-onset, with or without developmental delay, MIM#620465; Epilepsy; Intellectual Disability; microcephaly
Mendeliome v1.1111 ATP6V0C Zornitza Stark edited their review of gene: ATP6V0C: Changed phenotypes: Epilepsy, early-onset, with or without developmental delay, MIM#620465, Epilepsy, Intellectual Disability, microcephaly
Mendeliome v1.1111 FBXO31 Ain Roesley reviewed gene: FBXO31: Rating: AMBER; Mode of pathogenicity: None; Publications: 35019165, 24623383; Phenotypes: Intellectual developmental disorder, autosomal recessive 45 (MIM#615979); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1111 TBL1XR1 Achchuthan Shanmugasundram reviewed gene: TBL1XR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28687524, 37010288; Phenotypes: Pierpont syndrome, OMIM:602342; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1111 NEB Achchuthan Shanmugasundram reviewed gene: NEB: Rating: AMBER; Mode of pathogenicity: None; Publications: 12207937, 21798101, 33376055, 37010288; Phenotypes: Arthrogryposis multiplex congenita 6, OMIM:619334; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1111 ECEL1 Achchuthan Shanmugasundram reviewed gene: ECEL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 30131190, 37010288; Phenotypes: Arthrogryposis, distal, type 5D, OMIM:615065; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.1111 CCT5 Bryony Thompson edited their review of gene: CCT5: Added comment: Now two families reported with two different missense variants (Leu224Val and His147Arg).; Changed publications: 16399879, 25124038, 25345891, 33076433, 37237456
Mendeliome v1.1111 ZFHX4 Ain Roesley Phenotypes for gene: ZFHX4 were changed from Developmental disorders to neurodevelopmental disorder, ZFHX4-related (MONDO:0700092)
Mendeliome v1.1110 RNH1 Zornitza Stark Phenotypes for gene: RNH1 were changed from Neurodevelopmental disorder, MONDO:0700092, RNH1-related; encephalopathy, acute, infection-induced (MONDO:0000166), RNH1-related to Neurodevelopmental disorder, MONDO:0700092, RNH1-related; {Encephalopathy, acute, infection-induced, susceptibiliyt to, 12}, MIM# 620461
Mendeliome v1.1109 HNRNPC Zornitza Stark Marked gene: HNRNPC as ready
Mendeliome v1.1109 HNRNPC Zornitza Stark Gene: hnrnpc has been classified as Green List (High Evidence).
Mendeliome v1.1109 HNRNPC Zornitza Stark Classified gene: HNRNPC as Green List (high evidence)
Mendeliome v1.1109 HNRNPC Zornitza Stark Gene: hnrnpc has been classified as Green List (High Evidence).
Mendeliome v1.1108 HNRNPC Zornitza Stark gene: HNRNPC was added
gene: HNRNPC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HNRNPC was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNRNPC were set to 37541189
Phenotypes for gene: HNRNPC were set to Neurodevelopmental disorder (MONDO:0700092), HNRNPC-related
Review for gene: HNRNPC was set to GREEN
Added comment: 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five had an identical in-frame deletion of nine amino acids in the extreme C terminus. Supportive functional data; haploinsufficiency is the mechanism.
Sources: Literature
Mendeliome v1.1107 PSMC3 Zornitza Stark Phenotypes for gene: PSMC3 were changed from Deafness, cataract, impaired intellectual development, and polyneuropathy, MIM#619354 to neurodevelopmental disorder, MONDO:0700092, PSMC3-related; Deafness, cataract, impaired intellectual development, and polyneuropathy, MIM#619354
Mendeliome v1.1106 PSMC3 Zornitza Stark Publications for gene: PSMC3 were set to 32500975
Mendeliome v1.1105 PSMC3 Zornitza Stark Mode of inheritance for gene: PSMC3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1104 PSMC3 Zornitza Stark Classified gene: PSMC3 as Green List (high evidence)
Mendeliome v1.1104 PSMC3 Zornitza Stark Gene: psmc3 has been classified as Green List (High Evidence).
Mendeliome v1.1103 PSMC3 Zornitza Stark edited their review of gene: PSMC3: Added comment: PMID:37256937 - 23 individuals with neurodevelopmental disorder was identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program.; Changed rating: GREEN; Changed publications: 32500975, 37256937; Changed phenotypes: neurodevelopmental disorder, MONDO:0700092, PSMC3-related, Deafness, cataract, impaired intellectual development, and polyneuropathy, MIM#619354; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1103 EMC1 Zornitza Stark Publications for gene: EMC1 were set to 26942288; 29271071
Mendeliome v1.1102 EMC1 Zornitza Stark Mode of inheritance for gene: EMC1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1101 EMC1 Chern Lim edited their review of gene: EMC1: Changed rating: GREEN
Mendeliome v1.1101 EMC1 Chern Lim reviewed gene: EMC1: Rating: ; Mode of pathogenicity: None; Publications: 35234901, 26942288; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.1101 RELA Zornitza Stark Publications for gene: RELA were set to 28600438; 29305315
Mendeliome v1.1100 RELA Zornitza Stark Classified gene: RELA as Green List (high evidence)
Mendeliome v1.1100 RELA Zornitza Stark Gene: rela has been classified as Green List (High Evidence).
Mendeliome v1.1099 RELA Zornitza Stark changed review comment from: Additional 6 individuals from two families reported.; to: Additional 6 individuals from five families reported.
Mendeliome v1.1099 RELA Zornitza Stark edited their review of gene: RELA: Added comment: Additional 6 individuals from two families reported.; Changed rating: GREEN; Changed publications: 28600438, 29305315, 37273177; Changed phenotypes: Mucocutaneous ulceration, chronic, MIM# 618287, Impaired NFkB activation, reduced production of inflammatory cytokines, autoimmune cytopaenias
Mendeliome v1.1099 DPP9 Zornitza Stark Phenotypes for gene: DPP9 were changed from Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopenias to Hatipoglu immunodeficiency syndrome MIM#620331; Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopenias
Mendeliome v1.1098 DPP9 Zornitza Stark Phenotypes for gene: DPP9 were changed from Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopenias to Autoinflammatory syndrome MONDO:0019751, DPP9-related; recurrent fevers; repeated infections; herpes susceptibility; cytopenias
Mendeliome v1.1097 DPP9 Zornitza Stark Publications for gene: DPP9 were set to 36112693
Mendeliome v1.1096 DPP9 Zornitza Stark Mode of inheritance for gene: DPP9 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1095 DPP9 Zornitza Stark edited their review of gene: DPP9: Added comment: Amber for mono-allelic association:

de novo monoallelic dominant-negative mutation in DPP9 (c.755G>C, R252P) presenting with HLH at ~2m. Functional data supporting dominant negative mechanism.; Changed publications: 36112693, 37544411; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.1095 PDGFD Zornitza Stark Marked gene: PDGFD as ready
Mendeliome v1.1095 PDGFD Zornitza Stark Gene: pdgfd has been classified as Red List (Low Evidence).
Mendeliome v1.1095 PDGFD Zornitza Stark gene: PDGFD was added
gene: PDGFD was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: PDGFD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PDGFD were set to 33187088; 33971972
Phenotypes for gene: PDGFD were set to Pulmonary arterial hypertension MONDO:0015924, PDGFD-related
Review for gene: PDGFD was set to RED
Added comment: Rated as LIMITED by ClinGen. 10 unique variants (all missense) that have been reported in 10 probands in 2 publications (PMIDs: 33187088, 33971972) are included in this curation. 9 of these variants were observed in a cohort of 1647 idiopathic pulmonary arterial hypertension (IPAH) patients of European Ancestry as part of a case-control study. Variant aggregation analysis revealed a significant burden (p=0.0000172) of likely gene damaging PDGFD variants in the IPAH cohort as compared to a group of 18,819 European controls (PMID:33971972). Gelinas et al. also reported a missense PDGFD variant in a proband with IPAH (PMID:33187088). There is currently no functional evidence demonstrating a damaging effect of any of the reported PDGFD variants in humans.
Sources: Expert list
Mendeliome v1.1094 KLF2 Zornitza Stark Phenotypes for gene: KLF2 were changed from Pulmonary arterial hypertension to Pulmonary arterial hypertension MONDO:0015924, KLF2-related
Mendeliome v1.1093 KLF2 Zornitza Stark edited their review of gene: KLF2: Changed phenotypes: Pulmonary arterial hypertension MONDO:0015924, KLF2-related
Mendeliome v1.1093 FBLN2 Zornitza Stark Marked gene: FBLN2 as ready
Mendeliome v1.1093 FBLN2 Zornitza Stark Gene: fbln2 has been classified as Red List (Low Evidence).
Mendeliome v1.1093 FBLN2 Zornitza Stark gene: FBLN2 was added
gene: FBLN2 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: FBLN2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FBLN2 were set to 33971972
Phenotypes for gene: FBLN2 were set to Pulmonary arterial hypertension MONDO:0015924, FBLN2-related
Review for gene: FBLN2 was set to RED
Added comment: LIMITED by ClinGen. Out of a cohort of 1647 idiopathic PAH cases, 3 rare predicted deleterious missense variants were identified in 6 unrelated individuals with one variant recurrent in four individuals. Gene-disease association also supported by tissue expression data.
Sources: Expert list
Mendeliome v1.1092 AQP1 Zornitza Stark Phenotypes for gene: AQP1 were changed from Pulmonary arterial hypertension to Pulmonary arterial hypertension MONDO:0015924, AQP1-related
Mendeliome v1.1091 AQP1 Zornitza Stark Publications for gene: AQP1 were set to PMID:22683574; 29650961
Mendeliome v1.1090 AQP1 Zornitza Stark Classified gene: AQP1 as Amber List (moderate evidence)
Mendeliome v1.1090 AQP1 Zornitza Stark Gene: aqp1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.1089 AQP1 Zornitza Stark reviewed gene: AQP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 37007933, 35627312; Phenotypes: Pulmonary arterial hypertension MONDO:0015924, AQP1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1089 TET2 Zornitza Stark Phenotypes for gene: TET2 were changed from Dementia; Lymphoma/myeloid malignancy; Immunodeficiency-75 (IMD75), MIM#619126 to Dementia; Lymphoma/myeloid malignancy; Immunodeficiency-75 (IMD75), MIM#619126; Pulmonary arterial hypertension MONDO:0015924, TET2-related
Mendeliome v1.1088 TET2 Zornitza Stark Publications for gene: TET2 were set to 30890702; 31827242; 32330418
Mendeliome v1.1087 TET2 Zornitza Stark changed review comment from: Association with PAH:
MODERATE by ClinGen. TET2 was first reported in relation to autosomal dominant pulmonary arterial hypertension (PAH) in 2020 (Potus et al., PMID: 32192357). Out of a cohort of 2572 cases from the PAH biobank, 6 rare predicted deleterious likely germline variants including missense, nonsense, and frameshift variants were identified in 6 unrelated individuals. The relationship between TET2 and PAH is also supported by experimental evidence including tissue expression in controls and patients, biochemical function as a negative regulator of a proinflammatory response, and knock out TET2 mice exhibiting a PH phenotype.; to: Association with PAH:
MODERATE by ClinGen/Amber rating here. TET2 was first reported in relation to autosomal dominant pulmonary arterial hypertension (PAH) in 2020 (Potus et al., PMID: 32192357). Out of a cohort of 2572 cases from the PAH biobank, 6 rare predicted deleterious likely germline variants including missense, nonsense, and frameshift variants were identified in 6 unrelated individuals. The relationship between TET2 and PAH is also supported by experimental evidence including tissue expression in controls and patients, biochemical function as a negative regulator of a proinflammatory response, and knock out TET2 mice exhibiting a PH phenotype.
Mendeliome v1.1087 TET2 Zornitza Stark edited their review of gene: TET2: Added comment: Association with PAH:
MODERATE by ClinGen. TET2 was first reported in relation to autosomal dominant pulmonary arterial hypertension (PAH) in 2020 (Potus et al., PMID: 32192357). Out of a cohort of 2572 cases from the PAH biobank, 6 rare predicted deleterious likely germline variants including missense, nonsense, and frameshift variants were identified in 6 unrelated individuals. The relationship between TET2 and PAH is also supported by experimental evidence including tissue expression in controls and patients, biochemical function as a negative regulator of a proinflammatory response, and knock out TET2 mice exhibiting a PH phenotype.; Changed publications: 30890702, 31827242, 32330418, 32518946, 32192357; Changed phenotypes: Dementia, Lymphoma/myeloid malignancy, Immunodeficiency-75 (IMD75), MIM#619126, Pulmonary arterial hypertension MONDO:0015924, TET2-related
Mendeliome v1.1087 HNRNPA2B1 Zornitza Stark Phenotypes for gene: HNRNPA2B1 were changed from oculopharyngeal muscular dystrophy, MONDO:0008116; Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 MIM#615422 to oculopharyngeal muscular dystrophy, MONDO:0008116, OMIM#620460; Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 MIM#615422
Mendeliome v1.1086 AGAP1 Zornitza Stark Phenotypes for gene: AGAP1 were changed from Cerebral palsy to Cerebral palsy, MONDO:0006497, AGAP1-related
Mendeliome v1.1085 AGAP1 Zornitza Stark edited their review of gene: AGAP1: Changed phenotypes: Cerebral palsy, MONDO:0006497, AGAP1-related
Mendeliome v1.1085 PRDM10 Zornitza Stark Phenotypes for gene: PRDM10 were changed from Fibrofolliculoma, HP:0030436; lipomatosis, MONDO:0006574; renal cell carcinoma, MONDO:0005086 to Birt-Hogg-Dube syndrome 2, MIM# 620459
Mendeliome v1.1084 PRDM10 Zornitza Stark reviewed gene: PRDM10: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Birt-Hogg-Dube syndrome 2, MIM# 620459; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.1084 PLCB4 Zornitza Stark Phenotypes for gene: PLCB4 were changed from Auriculocondylar syndrome 2, MIM# 614669 to Auriculocondylar syndrome 2A, MIM# 614669; Auriculocondylar syndrome 2B, MIM# 620458
Mendeliome v1.1083 PLCB4 Zornitza Stark edited their review of gene: PLCB4: Changed phenotypes: Auriculocondylar syndrome 2A, MIM# 614669, Auriculocondylar syndrome 2B, MIM# 620458
Mendeliome v1.1083 IL1R1 Zornitza Stark Marked gene: IL1R1 as ready
Mendeliome v1.1083 IL1R1 Zornitza Stark Gene: il1r1 has been classified as Red List (Low Evidence).
Mendeliome v1.1083 IL1R1 Zornitza Stark gene: IL1R1 was added
gene: IL1R1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: IL1R1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IL1R1 were set to 37315560
Phenotypes for gene: IL1R1 were set to Chronic recurrent multifocal osteomyelitis 3, MIM# 259680
Review for gene: IL1R1 was set to RED
Added comment: Single individual reported with de novo missense variant in this gene and a phenotype of chronic recurrent multifocal osteomyelitis, auto inflammatory in nature. Some functional data presented.
Sources: Literature
Mendeliome v1.1082 STAB1 Zornitza Stark Marked gene: STAB1 as ready
Mendeliome v1.1082 STAB1 Zornitza Stark Gene: stab1 has been classified as Green List (High Evidence).
Mendeliome v1.1082 STAB1 Zornitza Stark Classified gene: STAB1 as Green List (high evidence)
Mendeliome v1.1082 STAB1 Zornitza Stark Gene: stab1 has been classified as Green List (High Evidence).
Mendeliome v1.1081 RINT1 Zornitza Stark Phenotypes for gene: RINT1 were changed from Recurrent acute liver failure to Infantile liver failure syndrome 3, MIM# 618641
Mendeliome v1.1080 SMARCA4 Zornitza Stark Phenotypes for gene: SMARCA4 were changed from Coffin-Siris syndrome 4, MIM# 614609 to Coffin-Siris syndrome 4, MIM# 614609; Otosclerosis MONDO:0005349, SMARCA4-related
Mendeliome v1.1079 SMARCA4 Zornitza Stark Publications for gene: SMARCA4 were set to 22426308
Mendeliome v1.1078 TBC1D31 Zornitza Stark Marked gene: TBC1D31 as ready
Mendeliome v1.1078 TBC1D31 Zornitza Stark Gene: tbc1d31 has been classified as Red List (Low Evidence).